Novel Pyrrole Inhibitors of S-Nitrosoglutathione Reductase as Therapeutic Agents

ABSTRACT

The present invention is directed to inhibitors of S-nitrosoglutathione reductase (GSNOR), pharmaceutical compositions comprising such GSNOR inhibitors, and methods of making and using the same.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Ser.No. 61/116,982, filed Nov. 21, 2008 and U.S. Provisional ApplicationSer. No. 61/089,313, filed Aug. 15, 2008. Each of these applications isincorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention is directed to novel pyrrole inhibitors ofS-nitrosoglutathione reductase, pharmaceutical compositions comprisingsuch inhibitors, and methods of making and using the same.

BACKGROUND OF THE INVENTION

The chemical compound nitric oxide is a gas with chemical formula NO. NOis one of the few gaseous signaling molecules known in biologicalsystems, and plays an important role in controlling various biologicalevents. For example, the endothelium uses NO to signal surroundingsmooth muscle in the walls of arterioles to relax, resulting invasodilation and increased blood flow to hypoxic tissues. NO is alsoinvolved in regulating smooth muscle proliferation, platelet function,neurotransmission, and plays a role in host defense. Although nitricoxide is highly reactive and has a lifetime of a few seconds, it canboth diffuse freely across membranes and bind to many molecular targets.These attributes make NO an ideal signaling molecule capable ofcontrolling biological events between adjacent cells and within cells.

NO is a free radical gas, which makes it reactive and unstable, thus NOis short lived in vivo, having a half life of 3-5 seconds underphysiologic conditions. In the presence of oxygen, NO can combine withthiols to generate a biologically important class of stable NO adductscalled S-nitrosothiols (SNO's). This stable pool of NO has beenpostulated to act as a source of bioactive NO and as such appears to becritically important in health and disease, given the centrality of NOin cellular homeostasis (Stamler et al., Proc. Natl. Acad. Sci. USA,89:7674-7677 (1992)). Protein SNO's play broad roles in cardiovascular,respiratory, metabolic, gastrointestinal, immune and central nervoussystem function (Foster et al., 2003, Trends in Molecular MedicineVolume 9, Issue 4, April 2003, pages 160-168). One of the most studiedSNO's in biological systems is S-nitrosoglutathione (GSNO) (Gaston etal., Proc. Natl. Acad. Sci. USA 90:10957-10961 (1993)), an emerging keyregulator in NO signaling since it is an efficient trans-nitrosatingagent and appears to maintain an equilibrium with other S-nitrosatedproteins (Liu et al., 2001) within cells. Given this pivotal position inthe NO-SNO continuum, GSNO provides a therapeutically promising targetto consider when NO modulation is pharmacologically warranted.

In light of this understanding of GSNO as a key regulator of NOhomeostasis and cellular SNO levels, studies have focused on examiningendogenous production of GSNO and SNO proteins, which occurs downstreamfrom the production of the NO radical by the nitric oxide synthetase(NOS) enzymes. More recently there has been an increasing understandingof enzymatic catabolism of GSNO which has an important role in governingavailable concentrations of GSNO and consequently available NO andSNO's.

Central to this understanding of GSNO catabolism, researchers haverecently identified a highly conserved S-nitrosoglutathione reductase(GSNOR) (Jensen et al., Biochem J., 331:659-668 (1998); Liu et al.,Nature, 410:490-494 (2001)). GSNOR is also known asglutathione-dependent formaldehyde dehydrogenase (GS-FDH), alcoholdehydrogenase 3 (ADH-3) (Uotila and Koivusalo, Coenzymes and Cofactors.,D. Dolphin, ed. pp. 517-551 (New York, John Wiley & Sons, 1989)), andalcohol dehydrogenase 5 (ADH-5). Importantly GSNOR shows greateractivity toward GSNO than other substrates (Jensen et al., 1998; Liu etal., 2001) and appears to mediate important protein and peptidedenitrosating activity in bacteria, plants, and animals. GSNOR appearsto be the major GSNO-metabolizing enzyme in eukaryotes (Liu et al.,2001). Thus, GSNO can accumulate in biological compartments where GSNORactivity is low or absent (e.g. airway lining fluid) (Gaston et al.,1993).

Yeast deficient in GSNOR accumulate S-nitrosylated proteins which arenot substrates of the enzyme, which is strongly suggestive that GSNOexists in equilibrium with SNO-proteins (Liu et al., 2001). Preciseenzymatic control over ambient levels of GSNO and thus SNO-proteinsraises the possibility that GSNO/GSNOR may play roles across a host ofphysiological and pathological functions including protection againstnitrosative stress wherein NO is produced in excess of physiologicneeds. Indeed, GSNO specifically has been implicated in physiologicprocesses ranging from the drive to breathe (Lipton et al., Nature,413:171-174 (2001)) to regulation of the cystic fibrosis transmembraneregulator (Zaman et al., Biochem Biophys Res Commun, 284:65-70 (2001),to regulation of vascular tone, thrombosis and platelet function (deBelder et al., Cardiovasc Res. 1994 May; 28(5):691-4. (1994); Z.Kaposzta, A et al., Circulation; 106(24): 3057-3062, 2002) as well ashost defense (de Jesus-Berrios et al., Curr. Biol., 13:1963-1968(2003)). Other studies have found that GSNOR protects yeast cellsagainst nitrosative stress both in vitro (Liu et al., 2001) and in vivo(de Jesus-Berrios et al., 2003).

Collectively data suggest GSNOR as a primary physiological ligand forthe enzyme S-nitrosoglutathione reductase (GSNOR), which catabolizesGSNO and consequently reduces available SNO's and NO in biologicalsystems (Liu et al., 2001), (Liu et al., Cell, (2004), 116(4), 617-628),and (Que et al., Science, 2005, 308, (5728):1618-1621). As such, thisenzyme plays a central role in regulating local and systemic bioactiveNO. Since perturbations in NO bioavailability has been linked to thepathogenesis of numerous disease states, including hypertension,atherosclerosis, thrombosis, asthma, gastrointestinal disorders,inflammation and cancer, agents that regulate GSNOR activity arecandidate therapeutic agents for treating diseases associated withnitric oxide imbalance.

Currently, there is a great need in the art for diagnostics,prophylaxis, ameliorations, and treatments for medical conditionsrelating to increased NO synthesis and/or increased NO bioactivity. Inaddition, there is a significant need for novel compounds, compositionsand methods for preventing, ameliorating, or reversing otherNO-associated disorders. The present invention satisfies these needs.

SUMMARY OF THE INVENTION

The present invention provides novel pyrrole compounds useful asS-nitrosoglutathione reductase (“GSNOR”) inhibitors. The inventionencompasses pharmaceutically acceptable salts, prodrugs, and metabolitesof the described GSNOR inhibitors. Also encompassed by the invention arepharmaceutical compositions comprising at least one GSNOR inhibitor andat least one pharmaceutically acceptable carrier.

The compositions of the present invention can be prepared in anysuitable pharmaceutically acceptable dosage form.

The present invention provides a method for inhibitingS-nitrosoglutathione reductase in a subject in need thereof. Such amethod comprises administering a therapeutically effective amount of apharmaceutical composition comprising at least one GSNOR inhibitor or apharmaceutically acceptable salt thereof, a prodrug or metabolitethereof, in combination with at least one pharmaceutically acceptablecarrier. The GSNOR inhibitor can be a novel compound according to theinvention, or it can be a known compound which previously was not knownto be an inhibitor of GSNOR.

The present invention also provides a method of treating a disorderameliorated by NO donor therapy in a subject in need thereof. Such amethod comprises administering a therapeutically effective amount of apharmaceutical composition comprising at least one GSNOR inhibitor or apharmaceutically acceptable salt thereof, a prodrug, or metabolitethereof, in combination with at least one pharmaceutically acceptablecarrier. The GSNOR inhibitor can be a novel compound according to theinvention, or it can be a known compound which previously was not knownto be an inhibitor of GSNOR.

The present invention also provides a method of treating a cellproliferative disorder in a subject in need thereof. Such a methodcomprises administering a therapeutically effective amount of apharmaceutical composition comprising at least one GSNOR inhibitor or apharmaceutically acceptable salt thereof, a prodrug, or metabolitethereof, in combination with at least one pharmaceutically acceptablecarrier. The GSNOR inhibitor can be a novel compound according to theinvention, or it can be a known compound which previously was not knownto be an inhibitor of GSNOR.

The methods of the invention encompass administration with one or moresecondary active agents. Such administration can be sequential or in acombination composition.

Although methods and materials similar or equivalent to those describedherein can be used in the practice or testing of the present invention,suitable methods and materials are described below. All publiclyavailable publications, patent applications, patents, and otherreferences mentioned herein are incorporated by reference in theirentirety. In the case of conflict, the present specification, includingdefinitions, will control.

Both the foregoing summary and the following detailed description areexemplary and explanatory and are intended to provide further details ofthe compositions and methods as claimed. Other objects, advantages, andnovel features will be readily apparent to those skilled in the art fromthe following detailed description.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS A. Overview of theInvention

Until recently, S-nitrosoglutathione reductase (GSNOR) was known tooxidize the formaldehyde glutathione adduct, S-hydroxymethylglutathione.GSNOR has since been identified in a variety of bacteria, yeasts, plantsand animals and is well conserved. The proteins from E. coli, S.cerevisiae and mouse macrophages share over 60% amino acid sequenceidentity. GSNOR activity (i.e., decomposition of S-nitrosoglutathionewhen NADH is present as a required cofactor) has been detected in E.coli, in mouse macrophages, in mouse endothelial cells, in mouse smoothmuscle cells, in yeasts, and in human HeLa, epithelial and monocytecells. Human GSNOR nucleotide and amino acid sequence information can beobtained from the National Center for Biotechnology Information (NCBI)databases under Accession Nos. M29872, NM_(—)000671. Mouse GSNORnucleotide and amino acid sequence information can be obtained from NCBIdatabases under Accession Nos. NM_(—)007410. In the nucleotide sequence,the start site and stop site are underlined. CDS designates codingsequence. SNP designates single nucleotide polymorphism. Other relatedGSNOR nucleotide and amino acid sequences, including those of otherspecies, can be found in U.S. Patent Application 2005/0014697.

In accord with the present invention, GSNOR has been shown to functionin vivo and in vitro to metabolize S-nitrosoglutathione (GSNO) andprotein S-nitrosothiols (SNOs) to modulate NO bioactivity, bycontrolling the intracellular levels of low mass NO donor compounds andpreventing protein nitrosylation from reaching toxic levels.

Based on this, it follows that inhibition of this enzyme potentiatesbioactivity in all diseases in which NO donor therapy is indicated,inhibits the proliferation of pathologically proliferating cells, andincreases NO bioactivity in diseases where this is beneficial.

The present invention provides pharmaceutical agents that are potentinhibitors of GSNOR. In particular, provided are substituted pyrroleanalogs that are inhibitors of GSNOR having the structures depictedbelow (Formula I-Formula IV), or a pharmaceutically acceptable salt,stereoisomer, or prodrug thereof.

Tri-substituted pyrrole analogs are potent inhibitors of GSNOR. As usedin this context, the term “analog” refers to a compound having similarchemical structure and function as compounds of formula I that retainsthe pyrrole ring.

Some pyrrole analogs of the invention can also exist in various isomericforms, including configurational, geometric and conformational isomers,as well as existing in various tautomeric forms, particularly those thatdiffer in the point of attachment of a hydrogen atom. As used herein,the term “isomer” is intended to encompass all isomeric forms of acompound including tautomeric forms of the compound.

Illustrative compounds having asymmetric centers can exist in differentenantiomeric and diastereomeric forms. A compound can exist in the formof an optical isomer or a diastereomer. Accordingly, the inventionencompasses compounds in the forms of their optical isomers,diastereomers and mixtures thereof, including racemic mixtures.

It should be noted that if there is a discrepancy between a depictedstructure and a name given to that structure, the depicted structurecontrols. In addition, if the stereochemistry of a structure or aportion of a structure is not indicated with, for example, bold, wedged,or dashed lines, the structure or portion of the structure is to beinterpreted as encompassing all stereoisomers of the described compound.

In accordance with the invention, the levels of the S-nitrosoglutathionereductase in the biological sample can be determined by the methodsdescribed in U.S. Patent Application Publication No. 2005/0014697. Theterm “biological sample” includes, but is not limited to, samples ofblood (e.g., serum, plasma, or whole blood), urine, saliva, sweat,breast milk, vaginal secretions, semen, hair follicles, skin, teeth,bones, nails, or other secretions, body fluids, tissues, or cells.

B. Definitions

As used herein, “about” will be understood by persons of ordinary skillin the art and will vary to some extent on the context in which it isused. If there are uses of the term which are not clear to persons ofordinary skill in the art given the context in which it is used, “about”will mean up to plus or minus 10% of the particular term.

The term “acyl” includes compounds and moieties that contain the acetylradical (CH₃CO—) or a carbonyl group to which a straight or branchedchain lower alkyl residue is attached.

The term “alkyl” as used herein refers to a straight or branched chain,saturated hydrocarbon having the indicated number of carbon atoms. Forexample, (C₁-C₆) alkyl is meant to include, but is not limited tomethyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl,isopentyl, neopentyl, hexyl, isohexyl, and neohexyl. An alkyl group canbe unsubstituted or optionally substituted with one or more substituentsas described herein.

The term “alkenyl” as used herein refers to a straight or branched chainunsaturated hydrocarbon having the indicated number of carbon atoms andat least one double bond. Examples of a (C₂-C₈) alkenyl group include,but are not limited to, ethylene, propylene, 1-butylene, 2-butylene,isobutylene, sec-butylene, 1-pentene, 2-pentene, isopentene, 1-hexene,2-hexene, 3-hexene, isohexene, 1-heptene, 2-heptene, 3-heptene,isoheptene, 1-octene, 2-octene, 3-octene, 4-octene, and isooctene. Analkenyl group can be unsubstituted or optionally substituted with one ormore substituents as described herein.

The term “alkynyl” as used herein refers to a straight or branched chainunsaturated hydrocarbon having the indicated number of carbon atoms andat least one triple bond. Examples of a (C₂-C₈) alkynyl group include,but are not limited to, acetylene, propyne, 1-butyne, 2-butyne,1-pentyne, 2-pentyne, 1-hexyne, 2-hexyne, 3-hexyne, 1-heptyne,2-heptyne, 3-heptyne, 1-octyne, 2-octyne, 3-octyne and 4-octyne. Analkynyl group can be unsubstituted or optionally substituted with one ormore substituents as described herein.

The term “alkoxy” as used herein refers to an —O-alkyl group having theindicated number of carbon atoms. For example, a (C₁-C₆) alkoxy groupincludes —O-methyl, —O-ethyl, —O-propyl, —O-isopropyl, —O-butyl,—O-sec-butyl, —O-tert-butyl, —O-pentyl, —O-isopentyl, —O-neopentyl,—O-hexyl, —O-isohexyl, and —O-neohexyl.

The term “aminoalkyl” as used herein, refers to an alkyl group(typically one to six carbon atoms) wherein one or more of the C₁-C₆alkyl group's hydrogen atoms is replaced with an amine of formula—N(R^(c))₂, wherein each occurrence of R^(c) is independently —H or(C₁-C₆) alkyl. Examples of aminoalkyl groups include, but are notlimited to, —CH₂NH₂, —CH₂CH₂NH₂—, —CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂CH₂NH₂,—CH₂CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂N(CH₃)₂,t-butylaminomethyl, isopropylaminomethyl and the like.

The term “aryl” as used herein refers to a 5- to 14-membered monocyclic,bicyclic or tricyclic aromatic ring system. Examples of an aryl groupinclude phenyl and naphthyl. An aryl group can be unsubstituted oroptionally substituted with one or more substituents as described hereinbelow. Examples of aryl groups include phenyl or aryl heterocycles suchas, pyrrole, furan, thiophene, thiazole, isothiazole, imidazole,triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine,pyridazine, and pyrimidine, and the like.

As used herein, the term “bioactivity” indicates an effect on one ormore cellular or extracellular process (e.g., via binding, signaling,etc.) which can impact physiological or pathophysiological processes.

The term “carbonyl” or “carboxy” or “carboxyl” includes compounds andmoieties which contain a carbon connected with a double bond to anoxygen atom. Examples of moieties containing a carbonyl include, but arenot limited to, aldehydes, ketones, carboxylic acids, amides, esters,anhydrides, etc.

The term “C_(m)-C_(n)” means “m” number of carbon atoms to “n” number ofcarbon atoms. For example, the term “C₁-C₆” means one to six carbonatoms (C₁, C₂, C₃, C₄, C₅ or C₆). The term “C₂-C₆” includes two to sixcarbon atoms (C₂, C₃, C₄, C₅ or C₆). The term “C₃-C₆” includes three tosix carbon atoms (C₃, C₄, C₅ or C₆).

The term “cycloalkyl” as used herein refers to a 3- to 14-memberedsaturated or unsaturated non-aromatic monocyclic, bicyclic or tricyclichydrocarbon ring system. Included in this class are cycloalkyl groupswhich are fused to a benzene ring. Representative cycloalkyl groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl,cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl,1,3-cyclohexadienyl, cycloheptyl, cycloheptenyl, 1,3-cycloheptadienyl,1,4-cycloheptadienyl, -1,3,5-cycloheptatrienyl, cyclooctyl,cyclooctenyl, 1,3-cyclooctadienyl, 1,4-cyclooctadienyl,-1,3,5-cyclooctatrienyl, decahydronaphthalene, octahydronaphthalene,hexahydronaphthalene, octahydroindene, hexahydroindene,tetrahydroindene, decahydrobenzocycloheptene,octahydrobenzocycloheptene, hexahydrobenzocycloheptene,tetrahydrobenzocyclopheptene, dodecahydroheptalene, decahydroheptalene,octahydroheptalene, hexahydroheptalene, and tetrahydroheptalene,(1s,3s)-bicyclo[1.1.0]butane, bicyclo[1.1.1]pentane,bicyclo[2.1.1]hexane, Bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane,bicyclo[3.1.1]heptane, bicyclo[3.2.1]octane, bicyclo[3.3.1]nonane,bicyclo[3.3.2]decane, bicyclo[3.3.]undecane, bicyclo[4.2.2]decane,bicyclo[4.3.1]decane. A cycloalkyl group can be unsubstituted oroptionally substituted with one or more substituents as described hereinbelow.

The term “halogen” includes fluorine, bromine, chlorine, iodine, etc.

The term “haloalkyl” as used herein, refers to a C₁-C₆ alkyl groupwherein from one or more of the C₁-C₆ alkyl group's hydrogen atom isreplaced with a halogen atom, which can be the same or different.Examples of haloalkyl groups include, but are not limited to,trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl,pentachloroethyl, and 1,1,1-trifluoro-2-bromo-2-chloroethyl.

The term “heteroalkyl” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chainalkyl, or combinations thereof, consisting of carbon atoms and from oneto three heteroatoms selected from the group consisting of O, N and S,and wherein the nitrogen and sulfur atoms may optionally be oxidized andthe nitrogen heteroatom may optionally be quaternized. The heteroatom(s)O, N and S can be placed at any position of the heteroalkyl group.Examples include —CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃,—CH₂—S—CH₂—CH₃, —CH₂—CH₂—S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, and—CH₂—CH═N—OCH₃. Up to two heteroatoms can be consecutive, such as, forexample, —CH₂—NH—OCH₃. When a prefix such as (C₂-C₈) is used to refer toa heteroalkyl group, the number of carbons (2 to 8, in this example) ismeant to include the heteroatoms as well. For example, a C₂-heteroalkylgroup is meant to include, for example, —CH₂OH (one carbon atom and oneheteroatom replacing a carbon atom) and —CH₂SH.

To further illustrate the definition of a heteroalkyl group, where theheteroatom is oxygen, a heteroalkyl group can be an oxyalkyl group. Forinstance, (C₂-C₅) oxyalkyl is meant to include, for example —CH₂—O—CH₃(a C₃-oxyalkyl group with two carbon atoms and one oxygen replacing acarbon atom), —CH₂CH₂CH₂CH₂OH, —OCH₂CH₂OCH₂CH₂OH, —OCH₂CH(OH)CH₂OH, andthe like.

The term “heteroaryl” as used herein refers to an aromatic heterocyclering of 5 to 14 members and having at least one heteroatom selected fromnitrogen, oxygen and sulfur, and containing at least 1 carbon atom,including monocyclic, bicyclic, and tricyclic ring systems.Representative heteroaryls are triazolyl, tetrazolyl, oxadiazolyl,pyridyl, furyl, benzofuranyl, thienyl (thiophen-yl), benzothienyl,quinolinyl, pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl,benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl,isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,cinnolinyl, phthalazinyl, quinazolinyl, pyrimidyl, azepinyl, oxepinyl,quinoxalinyl and oxazolyl. A heteroaryl group can be unsubstituted oroptionally substituted with one or more substituents as described hereinbelow.

As used herein, the term “heteroatom” is meant to include oxygen (O),nitrogen (N), and sulfur (S).

As used herein, the term “heterocycle” refers to 3- to 14-membered ringsystems which are either saturated, unsaturated, or aromatic, and whichcontains from 1 to 4 heteroatoms independently selected from nitrogen,oxygen and sulfur, and wherein the nitrogen and sulfur heteroatoms canbe optionally oxidized, and the nitrogen heteroatom can be optionallyquaternized, including, including monocyclic, bicyclic, and tricyclicring systems. The bicyclic and tricyclic ring systems may encompass aheterocycle or heteroaryl fused to a benzene ring. The heterocycle canbe attached via any heteroatom or carbon atom, where chemicallyacceptable. Heterocycles include heteroaryls as defined above.Representative examples of heterocycles include, but are not limited to,aziridinyl, oxiranyl, thiiranyl, triazolyl, tetrazolyl, azirinyl,diaziridinyl, diazirinyl, oxaziridinyl, azetidinyl, azetidinonyl,oxetanyl, thietanyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl,oxazinyl, thiazinyl, diazinyl, dioxanyl, triazinyl, tetrazinyl,imidazolyl, tetrazolyl, pyrrolidinyl, isoxazolyl, furanyl, furazanyl,pyridinyl, oxazolyl, benzoxazolyl, benzisoxazolyl, thiazolyl,benzthiazolyl, thienyl, pyrazolyl, triazolyl, pyrimidinyl,benzimidazolyl, isoindolyl, indazolyl, benzodiazolyl, benzotriazolyl,benzoxazolyl, benzisoxazolyl, purinyl, indolyl, isoquinolinyl,quinolinyl and quinazolinyl. A heterocycle group can be unsubstituted oroptionally substituted with one or more substituents as described hereinbelow.

The term “heterocycloalkyl” by itself or in combination with otherterms, represents, unless otherwise stated, cyclic versions of“heteroalkyl.” Additionally, a heteroatom can occupy the position atwhich the heterocycle is attached to the remainder of the molecule.Examples of heterocycloalkyl include 1-(1,2,5,6-tetrahydropyridyl),1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl,3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl,tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl,2-piperazinyl, and the like.

The term “hydroxyalkyl” as used herein, refers to an alkyl group havingthe indicated number of carbon atoms wherein one or more of the hydrogenatoms in the alkyl group is replaced with an —OH group. Examples ofhydroxyalkyl groups include, but are not limited to, —CH₂OH, —CH₂CH₂OH,—CH₂CH₂CH₂OH, —CH₂CH₂CH₂CH₂OH, —CH₂CH₂CH₂CH₂CH₂OH,—CH₂CH₂CH₂CH₂CH₂CH₂OH, and branched versions thereof.

The term “hydroxy” or “hydroxyl” includes groups with an —OH or —O⁻.

As used herein and unless otherwise indicated, the term “stereoisomer”means one stereoisomer of a compound that is substantially free of otherstereoisomers of that compound. For example, a stereomerically purecompound having one chiral center will be substantially free of theopposite enantiomer of the compound. A stereomerically pure compoundhaving two chiral centers will be substantially free of otherdiastereomers of the compound. In some embodiments, a stereomericallypure compound comprises greater than about 80% by weight of onestereoisomer of the compound and less than about 20% by weight of otherstereoisomers of the compound, for example greater than about 90% byweight of one stereoisomer of the compound and less than about 10% byweight of the other stereoisomers of the compound, or greater than about95% by weight of one stereoisomer of the compound and less than about 5%by weight of the other stereoisomers of the compound, or greater thanabout 97% by weight of one stereoisomer of the compound and less thanabout 3% by weight of the other stereoisomers of the compound.

As used herein, “protein” is used synonymously with “peptide,”“polypeptide,” or “peptide fragment.” A “purified” polypeptide, protein,peptide, or peptide fragment is substantially free of cellular materialor other contaminating proteins from the cell, tissue, or cell-freesource from which the amino acid sequence is obtained, or substantiallyfree from chemical precursors or other chemicals when chemicallysynthesized.

As used herein, “modulate” is meant to refer to an increase or decreasethe levels of a peptide or a polypeptide, or to increase or decrease thestability or activity of a peptide or a polypeptide. The term “inhibit”is meant to refer to a decrease in the levels of a peptide or apolypeptide or to decrease in the stability or activity of a peptide ora polypeptide. In preferred embodiments, the peptide which is modulatedor inhibited is S-nitrosoglutathione (GSNO) or protein S-nitrosothiols(SNOs).

As used here, the terms “nitric oxide” and “NO” encompass unchargednitric oxide and charged nitric oxide species, particularly includingnitrosonium ion (NO⁺) and nitroxyl ion (NO⁻). The reactive form ofnitric oxide can be provided by gaseous nitric oxide. Compounds havingthe structure X—NO_(y) wherein X is a nitric oxide releasing, deliveringor transferring moiety, including any and all such compounds whichprovide nitric oxide to its intended site of action in a form active fortheir intended purpose, and Y is 1 or 2.

As utilized herein, the term “pharmaceutically acceptable” meansapproved by a regulatory agency of a federal or a state government orlisted in the U.S. Pharmacopoeia or other generally recognizedpharmacopoeia for use in animals and, more particularly, in humans. Theterm “carrier” refers to a diluent, adjuvant, excipient, or vehicle withwhich the therapeutic is administered and includes, but is not limitedto such sterile liquids as water and oils.

A “pharmaceutically acceptable salt” or “salt” of a GSNOR inhibitor is aproduct of the disclosed compound that contains an ionic bond, and istypically produced by reacting the disclosed compound with either anacid or a base, suitable for administering to a subject. Apharmaceutically acceptable salt can include, but is not limited to,acid addition salts including hydrochlorides, hydrobromides, phosphates,sulphates, hydrogen sulphates, alkylsulphonates, arylsulphonates,arylalkylsulfonates, acetates, benzoates, citrates, maleates, fumarates,succinates, lactates, and tartrates; alkali metal cations such as Li,Na, K, alkali earth metal salts such as Mg or Ca, or organic aminesalts.

A “pharmaceutical composition” is a formulation comprising the disclosedcompounds in a form suitable for administration to a subject. Apharmaceutical composition of the invention is preferably formulated tobe compatible with its intended route of administration. Examples ofroutes of administration include, but are not limited to, oral andparenteral, e.g., intravenous, intradermal, subcutaneous, inhalation,topical, transdermal, transmucosal, and rectal administration.

The term “substituted” as used herein, means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valency isnot exceeded, and that the substitution results in a stable compound.When a substituent is keto (i.e., ═O), then 2 hydrogens on the atom arereplaced. Ring double bonds, as used herein, are double bonds that areformed between two adjacent ring atoms (e.g., C═C, C═N, or N═N).

Substituents for the groups referred to as alkyl, heteroalkyl, alkylene,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl andheterocycloalkenyl can be selected from a variety of groups including—OR^(d)′, ═O, ═NR^(d)′, ═N—OR^(d)′, —NR^(d)′R^(d)″, —SR^(d)′, -halo,—SiR^(d)′R^(d)″R^(d)″′, —OC(O)R^(d)′, —C(O)R^(d)′, —CO₂R^(d)′,—CONR^(d)′R^(d)″, —OC(O)NR^(d)′R^(d)″, —NR^(d)″C(O)R^(d)′,—NR^(d)″′C(O)NR^(d)′R^(d)″, —NR^(d)″′SO₂NR^(d)′R^(d)″,—NR^(d)″CO₂R^(d)′, —NHC(NH₂)═NH, —NR^(d)′C(NH₂)═NH, —NHC(NH₂)═NR^(d)′,—S(O)R^(d)′, —SO₂R^(d)′, —SO₂NR^(d)′R^(d)″, —NR^(d)″SO₂R^(d)′, —CN and—NO₂, in a number ranging from zero to three, with those groups havingzero, one or two substituents being exemplary.

R^(d)′, R^(d)″ and R^(d)′″ each independently refer to hydrogen,unsubstituted (C₁-C₈)alkyl, unsubstituted hetero(C₁-C₈)alkyl,unsubstituted aryl and aryl substituted with one to three substituentsselected from -halo, unsubstituted alkyl, unsubstituted alkoxy,unsubstituted thioalkoxy and unsubstituted aryl(C₁-C₄)alkyl. When R^(d)′and R^(d)″ are attached to the same nitrogen atom, they can be combinedwith the nitrogen atom to form a 5-, 6- or 7-membered ring. For example,—NR^(d)′R^(d)″ can represent 1-pyrrolidinyl or 4-morpholinyl.

Typically, an alkyl or heteroalkyl group will have from zero to threesubstituents, with those groups having two or fewer substituents beingexemplary of the present invention. An alkyl or heteroalkyl radical canbe unsubstituted or monosubstituted. In some embodiments, an alkyl orheteroalkyl radical will be unsubstituted.

Exemplary substituents for the alkyl and heteroalkyl radicals includebut are not limited to —OR^(d)′, ═O, ═NR^(d)′, ═N—OR^(d)′,—NR^(d)′R^(d)″, —SR^(d)′, -halo, —SiR^(d)′R^(d)″R^(d)″′, —OC(O)R^(d)′,—C(O)R^(d)′, —CO₂R^(d)′, —CONR^(d)′R^(d)″, —OC(O)NR^(d)′R^(d)″,—NR^(d)″C(O)R^(d)′, —NR^(d)″′C(O)NR^(d)′R^(d)″,—NR^(d)″′SO₂NR^(d)′R^(d)″, —NR^(d)″CO₂R^(d)′, —NHC(NH₂)═NH,—NR^(a)′C(NH₂)═NH, —NHC(NH₂)═NR^(d)′, —S(O)R^(d)′, —SO₂R^(d)′,—SO₂NR^(d)′R^(d)″, —NR^(d)″SO₂R^(d)′, —CN and —NO₂, where R^(d)′, R^(d)″and R^(d)″′ are as defined above. Typical substituents can be selectedfrom: —OR^(d)′, ═O, —NR^(d)′R^(d)″, -halo, —OC(O)R^(d)′, —CO₂R^(d)′,—C(O)NR^(d)′R^(d)″, —OC(O)NR^(d)′R^(d)″, —NR^(d)″C(O)R^(d)′,—NR^(d)″CO₂R^(d)′, —NR^(d)″′SO₂NR^(d)′R^(d)″, —SO₂R^(d)′,—SO₂NR^(d)′R^(d)″, —NR^(d)″SO₂R^(d)′, —CN and —NO₂.

Similarly, substituents for the aryl and heteroaryl groups are variedand selected from: -halo, —OR^(e)′, —OC(O)R^(e)′, —NR^(e)′R^(e)″,—SR^(e)′, —R^(e)′, —CN, —NO₂, —CO₂R^(e)′, —C(O)NR^(e)′R^(e)″,—C(O)R^(e)′, —OC(O)NR^(e)′R^(e)″, —NR^(e)″C(O)R^(e)′, —NR^(e)″CO₂R^(e)′,—NR^(e)″′C(O)NR^(e)′R^(e)″, —NR^(e)″′SO₂NR^(e)′R^(e)″, —NHC(NH₂)═NH,—NR^(e)′C(NH₂)═NH, —NH—C(NH₂)═NR^(e)′, —S(O)R^(e)′, —SO₂R^(e)′,—SO₂NR^(e)′R^(e)″, —NR^(e)″SO₂R^(e)′, —N₃, —CH(Ph)₂, perfluoroalkoxy andperfluoro(C₁-C₄)alkyl, in a number ranging from zero to the total numberof open valences on the aromatic ring system.

R^(e)′, R^(e)″ and R^(e)″′ are independently selected from hydrogen,unsubstituted (C₁-C₈) alkyl, unsubstituted hetero(C₁-C₈) alkyl,unsubstituted aryl, unsubstituted heteroaryl, unsubstituted aryl(C₁-C₄)alkyl and unsubstituted aryloxy(C₁-C₄) alkyl. Typically, an aryl orheteroaryl group will have from zero to three substituents, with thosegroups having two or fewer substituents being exemplary in the presentinvention. In one embodiment of the invention, an aryl or heteroarylgroup will be unsubstituted or monosubstituted. In another embodiment,an aryl or heteroaryl group will be unsubstituted.

Two of the substituents on adjacent atoms of an aryl or heteroaryl ringin an aryl or heteroaryl group as described herein may optionally bereplaced with a substituent of the formula -T-C(O)—(CH₂)_(q)—U—, whereinT and U are independently —NH—, —O—, —CH₂— or a single bond, and q is aninteger of from 0 to 2. Alternatively, two of the substituents onadjacent atoms of the aryl or heteroaryl ring may optionally be replacedwith a substituent of the formula -J-(CH₂)_(r)—K—, wherein J and K areindependently —CH₂—, —O—, —NH—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR^(f)′— ora single bond, and r is an integer of from 1 to 3. One of the singlebonds of the new ring so formed may optionally be replaced with a doublebond. Alternatively, two of the substituents on adjacent atoms of thearyl or heteroaryl ring may optionally be replaced with a substituent ofthe formula —(CH₂)_(s)—X—(CH₂)_(t)—, where s and t are independentlyintegers of from 0 to 3, and X is —O—, —NR^(f)′—, —S—, —S(O)—, —S(O)₂—,or —S(O)₂NR^(a)′—. The substituent R^(f)′ in —NR^(f)′— and—S(O)₂NR^(f)′— is selected from hydrogen or unsubstituted (C₁-C₆) alkyl.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

As used herein the term “therapeutically effective amount” generallymeans the amount necessary to ameliorate at least one symptom of adisorder to be prevented, reduced, or treated as described herein. Thephrase “therapeutically effective amount” as it relates to the GSNORinhibitors of the present invention shall mean the GSNOR inhibitordosage that provides the specific pharmacological response for which theGSNOR inhibitor is administered in a significant number of subjects inneed of such treatment. It is emphasized that a therapeuticallyeffective amount of a GSNOR inhibitor that is administered to aparticular subject in a particular instance will not always be effectivein treating the conditions/diseases described herein, even though suchdosage is deemed to be a therapeutically effective amount by those ofskill in the art.

C. S-Nitrosoglutathione Reductase Inhibitors

1. Inventive Compounds

In one of its aspects the present invention provides a compound having astructure shown in Formula I, or a pharmaceutically acceptable salt,stereoisomer, or prodrug thereof:

whereinAr is selected from the group consisting of aryl, substituted aryl,heteroaryl and substituted heteroaryl;R₁ is selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₃-C₆cycloalkyl, aryl, substituted aryl, heteroaryl, and substitutedheteroaryl;R₂ is selected from the group consisting of halogen, C₁-C₆ alkyl, C₃-C₆cycloalkyl, cyano, nitro, CF₃, carbamoyl, C₁-C₆ alkylcarbamoyl, amino,C₁-C₆ alkylamino, C₁-C₆ dialkylamino, C₁-C₆ alkoxyl, and C₃-C₆cycloalkoxy;R₃ is selected from the group consisting of hydroxyl, carbamoyl, C₁-C₆alkylcarbamoyl, sulfamoyl, C₁-C₆ alkylsulfamoyl, C₃-C₆ cycloalkyl,cyano, nitro, carboxyl, amino, aminomethyl, acetamido,acetamido-2-methyl, 2-methoxyacetamido, propionamido,tetrahydrofuran-2-ylmethoxy, CF₃, carboxyl, ureido, sulfamoylamino,C₁-C₆ alkylsulfonamido, 2-amino-2-oxoethyl, C₁-C₆ alkylamino, C₁-C₆dialkylamino, arylamino, heteroarylamino, C₁-C₆ alkoxyl, C₃-C₆cycloalkoxyl, 1H-imidazol-2-yl, oxazol-2-yl, thiazol-2-yl,methylcarbamoyl, dimethylcarbamoyl, methoxyethylcarbamoyl,hydroxyethylcarbamoyl, (dimethylamino)ethylcarbamoyl,pyridin-3-ylcarbamoyl, pyridin-4-yl-carbamoyl,6-methoxypyridin-3-ylcarbamoyl, pyridazin-4-ylcarbamoyl, andpyrimidin-5-ylcarbamoyl;R₄ is selected from the group consisting of hydrogen, hydroxyl, halogen,C₁-C₆ alkyl, C₃-C₆ cycloalkyl, cyano, nitro, carbamoyl, C₁-C₆alkylcarbamoyl, sulfamoyl, C₁-C₆ alkyl sulfamoyl, amino, C₁-C₆alkylamino, C₁-C₆ dialkylamino, C₁-C₆ alkoxyl, and C₃-C₆ cycloalkoxyl;n is 0-3;wherein Ar excludes substituted or unsubstituted indazol-3-yl andsubstituted or unsubstituted 1H-pyrazolo[3,4-b]pyridyl;with the following provisos:proviso Ia: when R₃ is carboxyl, methylsulfonamido, or sulfamoyl, thenAr cannot be phenyl, substituted or unsubstituted phenyl-(C₁-C₃)-alkyl,or phenyl-(C₂-C₆)-alkenyl; and proviso Ib: when R₂ and R₃ are bothmethoxy, then Ar cannot be phenyl, 4-methyl-phenyl, 4-methoxy-phenyl,4-halo-phenyl, or thiophen-yl.

In a further aspect of the invention of formula I, Ar is selected fromthe group consisting of phenyl, substituted phenyl, thiophen-yl,substituted thiophen-yl, pyridinyl, substituted pyridinyl, thiazolyl,substituted thiazolyl, pyrimidinyl, substituted pyrimidinyl, furanyl,substituted furanyl, bicyclic aryl, substituted bicyclic aryl, bicyclicheteroaryl, and substituted bicyclic heteroaryl;

R₁ is selected from the group consisting of hydrogen and C₁-C₆ alkyl;R₂ is selected from the group consisting of halogen, C₁-C₆ alkyl, andCF₃;R₃ is selected from the group consisting of hydroxyl, carbamoyl,sulfamoyl, sulfamoylamino, C₁-C₆ alkoxy, amino, aminomethyl, acetamido,acetamido-2-methyl, 2-methoxyacetamido, propionamido,tetrahydrofuran-2-ylmethoxy, methylsulfamido, carboxyl, C₁-C₆alkylamino, 1H-imidazol-2-yl, oxazol-2-yl, thiazol-2-yl,methylcarbamoyl, dimethylcarbamoyl, methoxyethylcarbamoyl,hydroxyethylcarbamoyl, (dimethylamino)ethylcarbamoyl,pyridin-3-ylcarbamoyl, pyridin-4-yl-carbamoyl,6-methoxypyridin-3-ylcarbamoyl, pyridazin-4-ylcarbamoyl, andpyrimidin-5-ylcarbamoyl;R₄ is selected from the group consisting of hydrogen and C₁-C₆ alkyl;andn is 1.

In a further aspect of the invention of formula I, Ar is selected fromthe group consisting of phenyl, substituted phenyl, aryl-phenyl,substituted aryl-phenyl, heteroaryl-phenyl, substitutedheteroaryl-phenyl, thiophen-yl, substituted thiophen-yl,aryl-thiophen-yl, substituted aryl-thiophen-yl, heteroaryl-thiophen-yl,substituted heteroaryl-thiophen-yl, pyridinyl, substituted pyridinyl,aryl-pyridinyl, substituted aryl-pyridinyl, heteroaryl-pyridinyl,substituted heteroaryl-pyridinyl, thiazolyl, substituted thiazolyl,aryl-thiazolyl; substituted aryl-thiazolyl; heteroaryl-thiazolyl;substituted heteroaryl-thiazolyl, pyrimidinyl, substituted pyrimidinyl,aryl-pyrimidinyl, substituted aryl-pyrimidinyl, heteroaryl-pyrimidinyl,substituted heteroaryl-pyrimidinyl, furanyl, substituted furanyl,aryl-furanyl, substituted aryl-furanyl, heteroaryl-furanyl, andsubstituted heteroaryl-furanyl.

In a further aspect of the invention of formula I, Ar is phenyl,thiophen-yl, thiazolyl, pyridinyl, pyrimidinyl, or furanyl having 0, 1,2, or 3 substitutions, wherein such substitutions are independentlyselected from the group consisting of hydrogen, hydroxyl, halogen, C₁-C₆alkoxy, amino, cyano, C₁-C₆ alkyl, imidazolyl, methyl imidazolyl, ethylimidazolyl, furanyl, methylthio, nitro, triazolyl, tetrazolyl,carbamoyl, pyrazolyl, trifluoromethoxy, trifluoromethyl,2-amino-2oxoethoxy, ureido, morpholino, pyridinyl, pyrrolyl, methylsulfonamido, carbamoyl phenyl, 6-oxo-1,6-dihydropyridinyl,3,5-dimethylisoxazolyl, carboxymethoxy, hydroxyacetamido,methoxyacetamido, sulfamoyl, piperazinyl, oxoimidazolidinyl,methylsulfinyl, methylsulfonyl, pyrrolidinyl, piperidinyl,methylpyrazolyl, phenyl, thiazolyl, hydroxycarbamoyl,cyclopropylimidazolyl, carboxy, methylamino, methoxymethyl,dimethylamino, hydroxymethylimidazolyl, oxooxazolidinyl, formamido,hydroxyphenyl, and thiophen-yl.

In a further aspect of the invention of formula I, Ar is selected fromthe group consisting of 4-(1H-imidazol-1-yl)phenyl,5-(1H-imidazol-1-yl)thiophen-2-yl, 4-(2-methyl-1H-imidazol-1-yl)phenyl,thiazol-5-yl, 4-hydroxyphenyl, 5-bromothiophen-2-yl, 4-methoxyphenyl,4-aminophenyl, 4-bromophenyl, 4-(furan-3-yl)phenyl, phenyl,3-chloro-4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-cyanophenyl,3-chloro-4-hydroxyphenyl, 4-methoxy-3-methylphenyl, 4-iodophenyl,3-methoxyphenyl, 6-methoxypyridin-3-yl, benzo[d]thiazol-6-yl,4-(methylthio)phenyl, 4-nitrophenyl, 4-(4H-1,2,4-triazol-4-yl)phenyl,4-(2H-tetrazol-5-yl)phenyl, benzo[d][1,3]dioxol-5-yl,6-(1H-imidazol-1-yl)pyridin-3-yl, 5-carbamoylthiophen-2-yl,4-(1H-pyrazol-4-yl)phenyl, 4-(trifluoromethoxy)phenyl,4-carbamoylphenyl, 4-(trifluoromethyl)phenyl,4-(1H-1,2,4-triazol-1-yl)phenyl, 4-(1H-pyrazol-1-yl)phenyl,4-(2-amino-2-oxoethoxy)phenyl, 4-(1-methyl-1H-pyrazol-4-yl)phenyl,4-(1H-tetrazol-1-yl)phenyl, 4-(4-methyl-1H-imidazol-1-yl)phenyl,4-ureidophenyl, 4-morpholinophenyl, 4-(2H-tetrazol-5-yl)phenyl,4-(pyridin-4-yl)phenyl, 4-(1H-pyrrol-1-yl)phenyl,4-(methylsulfonamido)phenyl, 1H-1,2,3-triazol-1-yl)phenyl,naphthalen-2-yl, 3′-carbamoylbiphenyl-4-yl,4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl,4-(3,5-dimethylisoxazol-4-yl)phenyl, 4-(pyridin-3-yl)phenyl,4-(carboxymethoxy)phenyl, 4-(2-hydroxyacetamido)phenyl,4-(2-methoxyacetamido)phenyl, 4-sulfamoylphenyl,4-(piperazin-1-yl)phenyl, 4-(2-oxoimidazolidin-1-yl)phenyl,4-ethoxyphenyl, 4-(methylsulfinyl)phenyl,4-(2-ethyl-1H-imidazol-1-yl)phenyl, 4-(furan-2-yl)phenyl,4-(methylsulfonyl)phenyl, 4-(pyrrolidin-1-yl)phenyl,4-(piperidin-1-yl)phenyl, 4-(1-methyl-1H-pyrazol-5-yl)phenyl,5-(2-methyl-1H-imidazol-1-yl)thiophen-2-yl, 4-(furan-3-yl)phenyl,2-methoxypyrimidin-5-yl, 2-methyl-4-(methylsulfonamido)phenyl,4-amino-3-chlorophenyl, 3,4-difluorophenyl, 2,4-difluorophenyl,4-chlorophenyl, 4-bromothiophen-2-yl, biphenyl-4-yl,2-(1H-imidazol-1-yl)pyrimidin-5-yl, 4-fluoro-3-methoxyphenyl,3-cyano-4-fluorophenyl, 4-carbamoyl-2-methylphenyl,4-methoxy-2-methylphenyl, 4-chloro-2-fluorophenyl, 4-fluorophenyl,4-fluoro-2-methylphenyl, 4-chloro-2-(trifluoromethyl)phenyl,4-chloro-2-methoxyphenyl, 4-cyano-3-fluorophenyl,2-chloro-4-methoxyphenyl, 4-(1H-imidazol-1-yl)thiophen-2-yl,3,5-dimethyl-4-nitrophenyl, 4-amino-3,5-dimethylphenyl,2-(1H-imidazol-1-yl)thiazol-4-yl, 2-ethoxy-4-fluorophenyl,4-methoxy-2-(trifluoromethyl)phenyl, 4-fluoro-2-methoxyphenyl,4-(thiazol-5-yl)phenyl, 4-chloro-3-fluorophenyl,4-(hydroxycarbamoyl)phenyl, 3-fluoro-4-(1H-imidazol-1-yl)phenyl,3-fluoro-4-(2-methyl-1H-imidazol-1-yl)phenyl, 4-chloro-2-ethoxyphenyl,5-bromo-2-methoxyphenyl, 4-(2-cyclopropyl-1H-imidazol-1-yl)phenyl,4-(2-methyl-1H-imidazol-1-yl)thiophen-2-yl, 4-bromo-2-methoxyphenyl,2-methoxy-4-(2-methyl-1H-imidazol-1-yl)phenyl, 4-chloro-2-hydroxyphenyl,5-bromothiophen-3-yl, 4-hydroxy-3-methylphenyl,2-carbamoyl-4-chlorophenyl, 2-acetamido-4-chlorophenyl, 2-methoxyphenyl,benzoic acid, 2,4-dimethoxyphenyl, 4-chloro-2-propoxyphenyl,4-chloro-2-(2-methoxyacetamido)phenyl,4-chloro-2-(methylsulfonamido)phenyl, 4-chloro-2-(methylamino)phenyl,4-chloro-2-(methoxymethyl)phenyl, 4-hydroxy-2-methoxyphenyl,4-chloro-2-(dimethylamino)phenyl,4-(2-(hydroxymethyl)-1H-imidazol-1-yl)phenyl,4-(2-oxooxazolidin-3-yl)phenyl)-1H-pyrrol-2-yl,4-(1H-imidazol-1-yl)-2-methoxyphenyl,5-(2-methyl-1H-imidazol-1-yl)thiophen-3-yl, 5-chlorothiophen-2-yl,5-bromothiazol-2-yl, 4-bromothiazol-2-yl,5-(2-ethyl-1H-imidazol-1-yl)thiophen-2-yl, 4-chloro-2-formamidophenyl,3-chlorothiophen-2-yl, 4-formamido-2-methoxyphenyl,3-bromo-5-methoxythiophen-2-yl, 5-(4-hydroxyphenyl)thiophen-2-yl,4-(thiophen-3-yl)phenyl, 5-(1H-imidazol-1-yl)furan-2-yl,4-chlorothiophen-2-yl, 5-bromo-4-chlorothiophen-2-yl,5-(2-methyl-1H-imidazol-1-yl)furan-2-yl, and 5-bromofuran-2-yl.

In a further aspect of the invention of formula I, Ar is selected fromthe group consisting of 4-(1H-imidazol-1-yl)phenyl,5-(1H-imidazol-1-yl)thiophen-2-yl, 4-(2-methyl-1H-imidazol-1-yl)phenyl,thiazol-5-yl, 4-hydroxyphenyl, 5-bromothiophen-2-yl, 4-methoxyphenyl,4-aminophenyl, 4-bromophenyl, 4-(furan-3-yl)phenyl,3-chloro-4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-cyanophenyl,3-chloro-4-hydroxyphenyl, 4-methoxy-3-methylphenyl, 4-iodophenyl,3-methoxyphenyl, 6-methoxypyridin-3-yl, benzo[d]thiazol-6-yl,4-(methylthio)phenyl, 4-nitrophenyl, 4-(4H-1,2,4-triazol-4-yl)phenyl,4-(2H-tetrazol-5-yl)phenyl, benzo[d][1,3]dioxol-5-yl,6-(1H-imidazol-1-yl)pyridin-3-yl, 5-carbamoylthiophen-2-yl,4-(1H-pyrazol-4-yl)phenyl, 4-(trifluoromethoxy)phenyl,4-carbamoylphenyl, 4-(trifluoromethyl)phenyl,4-(1H-1,2,4-triazol-1-yl)phenyl, 4-(1H-pyrazol-1-yl)phenyl,4-(2-amino-2-oxoethoxy)phenyl, 4-(1-methyl-1H-pyrazol-4-yl)phenyl,4-(1H-tetrazol-1-yl)phenyl, 4-(4-methyl-1H-imidazol-1-yl)phenyl,4-ureidophenyl, 4-morpholinophenyl, 4-(2H-tetrazol-5-yl)phenyl,4-(pyridin-4-yl)phenyl, 4-(1H-pyrrol-1-yl)phenyl,4-(methylsulfonamido)phenyl, 1H-1,2,3-triazol-1-yl)phenyl,naphthalen-2-yl, 3′-carbamoylbiphenyl-4-yl,4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl,4-(3,5-dimethylisoxazol-4-yl)phenyl, 4-(pyridin-3-yl)phenyl,4-(carboxymethoxy)phenyl, 4-(2-hydroxyacetamido)phenyl,4-(2-methoxyacetamido)phenyl, 4-sulfamoylphenyl,4-(piperazin-1-yl)phenyl, 4-(2-oxoimidazolidin-1-yl)phenyl,4-ethoxyphenyl, 4-(methylsulfinyl)phenyl,4-(2-ethyl-1H-imidazol-1-yl)phenyl, 4-(furan-2-yl)phenyl,4-(methylsulfonyl)phenyl, 4-(pyrrolidin-1-yl)phenyl,4-(piperidin-1-yl)phenyl, 4-(1-methyl-1H-pyrazol-5-yl)phenyl,5-(2-methyl-1H-imidazol-1-yl)thiophen-2-yl, 4-(furan-3-yl)phenyl,2-methoxypyrimidin-5-yl, 2-methyl-4-(methylsulfonamido)phenyl,4-amino-3-chlorophenyl, 3,4-difluorophenyl, 2,4-difluorophenyl,4-chlorophenyl, 4-bromothiophen-2-yl, biphenyl-4-yl,2-(1H-imidazol-1-yl)pyrimidin-5-yl, 4-fluoro-3-methoxyphenyl,3-cyano-4-fluorophenyl, 4-carbamoyl-2-methylphenyl,4-methoxy-2-methylphenyl, 4-chloro-2-fluorophenyl, 4-fluorophenyl,4-fluoro-2-methylphenyl, 4-chloro-2-(trifluoromethyl)phenyl,4-chloro-2-methoxyphenyl, 4-cyano-3-fluorophenyl,2-chloro-4-methoxyphenyl, 4-(1H-imidazol-1-yl)thiophen-2-yl,3,5-dimethyl-4-nitrophenyl, 4-amino-3,5-dimethylphenyl,2-(1H-imidazol-1-yl)thiazol-4-yl, 2-ethoxy-4-fluorophenyl,4-methoxy-2-(trifluoromethyl)phenyl, 4-fluoro-2-methoxyphenyl,4-(thiazol-5-yl)phenyl, 4-chloro-3-fluorophenyl,4-(hydroxycarbamoyl)phenyl, 3-fluoro-4-(1H-imidazol-1-yl)phenyl,3-fluoro-4-(2-methyl-1H-imidazol-1-yl)phenyl, 4-chloro-2-ethoxyphenyl,5-bromo-2-methoxyphenyl, 4-(2-cyclopropyl-1H-imidazol-1-yl)phenyl,4-(2-methyl-1H-imidazol-1-yl)thiophen-2-yl, 4-bromo-2-methoxyphenyl,2-methoxy-4-(2-methyl-1H-imidazol-1-yl)phenyl, 4-chloro-2-hydroxyphenyl,5-bromothiophen-3-yl, 4-hydroxy-3-methylphenyl,2-carbamoyl-4-chlorophenyl, 2-acetamido-4-chlorophenyl, 2-methoxyphenyl,benzoic acid, 2,4-dimethoxyphenyl, 4-chloro-2-propoxyphenyl,4-chloro-2-(2-methoxyacetamido)phenyl,4-chloro-2-(methylsulfonamido)phenyl, 4-chloro-2-(methylamino)phenyl,4-chloro-2-(methoxymethyl)phenyl, 4-hydroxy-2-methoxyphenyl,4-chloro-2-(dimethylamino)phenyl,4-(2-(hydroxymethyl)-1H-imidazol-1-yl)phenyl,4-(2-oxooxazolidin-3-yl)phenyl)-1H-pyrrol-2-yl,4-(1H-imidazol-1-yl)-2-methoxyphenyl,5-(2-methyl-1H-imidazol-1-yl)thiophen-3-yl, 5-chlorothiophen-2-yl,5-bromothiazol-2-yl, 4-bromothiazol-2-yl,5-(2-ethyl-1H-imidazol-1-yl)thiophen-2-yl, 4-chloro-2-formamidophenyl,3-chlorothiophen-2-yl, 4-formamido-2-methoxyphenyl,3-bromo-5-methoxythiophen-2-yl, 5-(4-hydroxyphenyl)thiophen-2-yl,4-(thiophen-3-yl)phenyl, 5-(1H-imidazol-1-yl)furan-2-yl,4-chlorothiophen-2-yl, 5-bromo-4-chlorothiophen-2-yl,5-(2-methyl-1H-imidazol-1-yl)furan-2-yl, and 5-bromofuran-2-yl.

In a further aspect of the invention of formula I, Ar is selected fromthe group consisting of aryl, substituted aryl, heteroaryl andsubstituted heteroaryl;

R₁ is selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₃-C₆cycloalkyl, aryl, substituted aryl, heteroaryl, and substitutedheteroaryl;R₂ is selected from the group consisting of halogen, hydroxyl, C₁-C₆alkyl, C₃-C₆ cycloalkyl, cyano, nitro, CF₃, carbamoyl, C₁-C₆alkylcarbamoyl, amino, C₁-C₆ alkylamino, C₁-C₆ dialkylamino, C₁-C₆alkoxyl, and C₃-C₆ cycloalkoxyl;R₃ is selected from the group consisting of halogen, hydroxyl,carbamoyl, substituted carbamoyl, C₁-C₆ alkylcarbamoyl, sulfamoyl, C₁-C₆alkylsulfamoyl, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, cyano, nitro, carboxyl,amino, aminomethyl, acetamido, acetamido-2-methyl, 2-methoxyacetamido,propionamido, tetrahydrofuran-2-ylmethoxy, CF₃, carboxyl, ureido,sulfamoylamino, C₁-C₆ alkylsulfonamido, 2-amino-2-oxoethyl, C₁-C₆alkylamino, C₁-C₆ dialkylamino, arylamino, heteroarylamino, C₁-C₆alkoxyl, C₃-C₆ cycloalkoxyl, aryl, substituted aryl, heteroaryl, andsubstituted heteroaryl;R₄ is selected from the group consisting of hydrogen, hydroxyl, halogen,C₁-C₆ alkyl, C₃-C₆ cycloalkyl, cyano, nitro, carbamoyl, C₁-C₆alkylcarbamoyl, sulfamoyl, C₁-C₆ alkyl sulfamoyl, amino, C₁-C₆alkylamino, C₁-C₆ dialkylamino, C₁-C₆ alkoxyl, and C₃-C₆ cycloalkoxyl;n is 0-3;with the following provisos:proviso Ia: Ar excludes substituted or unsubstituted indazol-3-yl andsubstituted or unsubstituted 1H-pyrazolo[3,4-b]pyridyl; andproviso Ib: when one of R₂, R₃, or R₄, are carboxyl, methylsulfonamido,hydroxycarbamoyl, methoxycarbamoyl, benzyloxycarbamoyl, sulfamoyl,1-H-tetrazol, 1-H-tetrazol-5-ylcarbamoyl,2-(trifluoromethylsulfonyl)hydrazinecarbonyl,1-carboxy-2-phenylethylcarbamoyl, 2-(carboxy)pyrrolidine-1-carbonyl,substituted or unsubstituted 3-(carboxy)thiophen-2-yl, substituted orunsubstituted 3-(carboxy)furan-2-yl, substituted or unsubstituted3-(carboxy)-1H-pyrrol-2-yl, 5-(trifluoromethyl)-1H-1,2,4-triazol-2-yl,5-substituted-1H-1,2,3-triazol-4-yl, Ar cannot be phenyl, substituted orunsubstituted phenyl-(C₁-C₃)-alkyl, or phenyl-(C₂-C₆)-alkenyl; andproviso Ic: when R₂ and R₃ are independently selected from the groupconsisting of halogen or methyl, Ar cannot be 4-hydroxyphenyl or 4-C₁-C₆acyl-oxy-phenyl; andproviso Id: when R₂ is hydroxyl, R₃ or R₄ cannot be Cl; andproviso Ie: when R₂ and R₃ are independently selected from the groupconsisting of Cl, methyl, and methoxy, then Ar cannot be phenyl,4-methyl-phenyl, 4-methoxy-phenyl, 4-halo-phenyl, or thiophen-yl.

In one of its aspects the present invention provides a compound having astructure shown in Formula II, or a pharmaceutically acceptable salt,stereoisomer, or prodrug thereof:

whereinAr is selected from the group consisting of aryl, substituted aryl,heteroaryl and substituted heteroaryl;R₁ is selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₃-C₆cycloalkyl, aryl, substituted aryl, heteroaryl, and substitutedheteroaryl;X₁-X₄ is independently selected from the group consisting of C and N;R₅ is selected from the group consisting of hydrogen, hydroxyl, halogen,C₁-C₆ alkyl, C₃-C₆ cycloalkyl, cyano, nitro, carbamoyl, C₁-C₆alkylcarbamoyl, carboxyl, C₁-C₆ alkylhydroxy, sulfamoyl, C₁-C₆alkylsulfamoyl, amino, C₁-C₆ alkylamino, C₁-C₆ dialkylamino, C₁-C₆alkoxyl, and C₃-C₆ cycloalkoxyl;R₆ is selected from the group consisting of halogen, hydroxyl,carbamoyl, substituted carbamoyl, C₁-C₆ alkylcarbamoyl, sulfamoyl, C₁-C₆alkylsulfamoyl, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, cyano, nitro, amino, CF₃,carboxyl, ureido, sulfamoylamino, 2-amino-2-oxoethyl, C₁-C₆ alkylamino,C₁-C₆ dialkylamino, arylamino, heteroarylamino, C₁-C₆ alkoxyl, C₃-C₆cycloalkoxyl, 1H-imidazol-1-yl, and 2-methyl-1H-imidazol-1-yl;or alternatively R₅ and R₆ together form a substituted or unsubstituted5 or 6 membered heterocyclic ring containing up to 2 heteroatoms chosenfrom O, N or S;R₇ is selected from the group consisting of hydrogen, hydroxyl, halogen,C₁-C₆ alkyl, C₃-C₆ cycloalkyl, cyano, nitro, carbamoyl, C₁-C₆alkylcarbamoyl, sulfamoyl, C₁-C₆ alkylsulfamoyl, amino, C₁-C₆alkylamino, C₁-C₆ dialkylamino, C₁-C₆ alkoxyl, and C₃-C₆ cycloalkoxyl;n is 0-3;wherein R₅ can be hydrogen only when at least one of X₁-X₄ is N;and further wherein, X₁ and X₃ must be CH or N unless R₅ and R₆ togetherform a 5 or 6 membered heterocyclic ring or at least one of X₁-X₄ is N;and wherein Ar excludes substituted or unsubstituted indazol-3-yl andsubstituted or unsubstituted 1H-pyrazolo[3,4-b]pyridyl;with the following provisos:proviso IIa: when all X are C and one of R₅, R₆, or R₇ are carboxyl,methylsulfonamido, or sulfamoyl, then Ar cannot be phenyl, substitutedor unsubstituted phenyl-(C₁-C₃)-alkyl, or phenyl-(C₂-C₆)-alkenyl; andproviso IIb: when all X are C and one of R₅, R₆, or R₇ are independentlyselected from the group consisting of halogen or methyl, then Ar cannotbe 4-hydroxyphenyl or 4-C₁-C₆ acyl-oxyphenyl; andproviso IIc: when all X are C and R₅ is methyl, Cl, hydroxyl,trifluoromethyl and R₆ is methyl, methyoxy, carboxyethyl, Cl, orcarboxypropyl, and n is 1, then Ar cannot be phenyl, 4-methyl-phenyl,4-methoxy-phenyl, 4-halo-phenyl, or thiophen-yl; andproviso IId: when all X are C and R₅ and R₆ together form a heterocyclicring and the resulting bicyclic ring system is benzo[d]thiazolsubstituted at the 2 position with C₁-C₃ alkyl, then Ar cannot bephenyl, 4-F-phenyl, 4-methoxy-phenyl, or thiophen-yl.

In a further aspect of the invention of formula II, Ar is selected fromthe group consisting of phenyl, substituted phenyl, thiophen-yl,substituted thiophen-yl, pyridinyl, substituted pyridinyl, thiazolyl,and substituted thiazolyl.

In a further aspect of the invention of formula II, Ar is selected fromthe group consisting of aryl, substituted aryl, heteroaryl andsubstituted heteroaryl;

R₁ is selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₃-C₆cycloalkyl, aryl, substituted aryl, heteroaryl, and substitutedheteroaryl;X₁-X₄ is independently selected from the group consisting of C and N;R₅ is selected from the group consisting of hydrogen, hydroxyl, halogen,C₁-C₆ alkyl, C₃-C₆ cycloalkyl, cyano, nitro, carbamoyl, C₁-C₆alkylcarbamoyl, carboxyl, C₁-C₆ alkylhydroxy, sulfamoyl, C₁-C₆alkylsulfamoyl, amino, C₁-C₆ alkylamino, C₁-C₆ dialkylamino, C₁-C₆alkoxyl, and C₃-C₆ cycloalkoxyl;R₆ is selected from the group consisting of halogen, hydroxyl,carbamoyl, substituted carbamoyl, C₁-C₆ alkylcarbamoyl, sulfamoyl, C₁-C₆alkylsulfamoyl, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, cyano, nitro, amino, CF₃,carboxyl, ureido, sulfamoylamino, 2-amino-2-oxoethyl, C₁-C₆ alkylamino,C₁-C₆ dialkylamino, arylamino, heteroarylamino, C₁-C₆ alkoxyl, C₃-C₆cycloalkoxyl, aryl, substituted aryl, heteroaryl, and substitutedheteroaryl;or alternatively R₅ and R₆ together form a substituted or unsubstituted5 or 6 membered heterocyclic ring containing up to 2 heteroatoms chosenfrom O, N or S;R₇ is selected from the group consisting of hydrogen, hydroxyl, halogen,C₁-C₆ alkyl, C₃-C₆ cycloalkyl, cyano, nitro, carbamoyl, C₁-C₆alkylcarbamoyl, sulfamoyl, C₁-C₆ alkylsulfamoyl, amino, C₁-C₆alkylamino, C₁-C₆ dialkylamino, C₁-C₆ alkoxyl, and C₃-C₆ cycloalkoxyl;n is 0-3;wherein R₅ can be hydrogen only when at least one of X₁-X₄ is N;and further wherein, X₁ and X₃ must be CH or N unless R₅ and R₆ togetherform a 5 or 6 membered heterocyclic ring or at least one of X₁-X₄ is N;with the following provisos:proviso IIa: Ar excludes substituted or unsubstituted indazol-3-yl andsubstituted or unsubstituted 1H-pyrazolo[3,4-b]pyridyl; andproviso IIb: when all X are C and one of R₅, R₆, or R₇ are carboxyl,methylsulfonamido, hydroxycarbamoyl, methoxycarbamoyl,benzyloxycarbamoyl, sulfamoyl, 1-H-tetrazol, 1-H-tetrazol-5-ylcarbamoyl,2-(trifluoromethylsulfonyl)hydrazinecarbonyl,1-carboxy-2-phenylethylcarbamoyl, 2-(carboxy)pyrrolidine-1-carbonyl,substituted or unsubstituted 3-(carboxy)thiophen-2-yl, substituted orunsubstituted 3-(carboxy)furan-2-yl, substituted or unsubstituted3-(carboxy)-1H-pyrrol-2-yl, 5-(trifluoromethyl)-1H-1,2,4-triazol-2-yl,5-substituted-1H-1,2,3-triazol-4-yl, Ar cannot be phenyl, substituted orunsubstituted phenyl-(C₁-C₃)-alkyl, or phenyl-(C₂-C₆)-alkenyl; andproviso IIc: when all X are C and one of R₅, R₆, or R₇ are independentlyselected from the group consisting of halogen or methyl, Ar cannot be4-hydroxyphenyl or 4-C₁-C₆ acyl-oxy-phenyl; andproviso IId: when all X are C and R₅ is methyl, Cl, hydroxyl,trifluoromethyl and R₆ is methyl, methyoxy, carboxyethyl, Cl, orcarboxypropyl, and n is 1, then Ar cannot be phenyl, 4-methyl-phenyl,4-methoxy-phenyl, 4-halo-phenyl, or thiophen-yl; andproviso IIe: when all X are C and R₅ and R₆ together form a heterocyclicring and the resulting bicyclic ring system is benzo[d]thiazolsubstituted at the 2 position with C₁-C₃ alkyl, then Ar cannot bephenyl, 4-F-phenyl, 4-methoxy-phenyl, or thiophen-yl.

In one of its aspects the present invention provides a compound having astructure shown in Formula III, or a pharmaceutically acceptable salt,stereoisomer, or prodrug thereof:

Ar is selected from the group consisting of aryl, substituted aryl,heteroaryl and substituted heteroaryl;R₁ is selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₃-C₆cycloalkyl, aryl, substituted aryl, heteroaryl, and substitutedheteroaryl;X₅-X₈ are independently selected from the group consisting of N, C andS, wherein at least one X must be N or S;R₈ and R₉ are independently selected from the group consisting ofhydrogen, halogen, hydroxyl, carbamoyl, substituted carbamoyl,sulfamoyl, substituted sulfamoyl, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, cyano,nitro, amino, CF₃, carboxyl, ureido, sulfamoylamino, 2-amino-2-oxoethyl,C₁-C₆ alkylamino, C₁-C₆ dialkylamino, arylamino, heteroarylamino, C₁-C₆alkoxyl, C₃-C₆ cycloalkoxyl, aryl, aryloxyl, substituted aryl,heteroaryl, substituted heteroaryl, and null if X₅-X₈ are all N;n is 0-3;wherein Ar excludes substituted or unsubstituted indazol-3-yl andsubstituted or unsubstituted 1H-pyrazolo[3,4-b]pyridyl.

In a further aspect of the invention of formula III, Ar is selected fromthe group consisting of phenyl, substituted phenyl, thiophen-yl,substituted thiophen-yl, pyridinyl, substituted pyridinyl, thiazolyl,substituted thiazolyl, bicyclic aryl, substituted bicyclic aryl,bicyclic heteroaryl, and substituted bicyclic heteroaryl.

In one of its aspects the present invention provides a compound having astructure shown in Formula IV, or a pharmaceutically acceptable salt,stereoisomer, or prodrug thereof:

whereinAr is selected from the group consisting of aryl, substituted aryl,heteroaryl and substituted heteroaryl;R₁ is selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₃-C₆cycloalkyl, aryl, substituted aryl, heteroaryl, and substitutedheteroaryl;R₁₀ is hydroxyl, carbamoyl, ureido, sulfamoylamino, 2-amino-2-oxoethyl,acetyl, hydroxyethyl, pyridin-3-ylamino, pyridin-4-ylamino,1-methylpyrrolidin-3-yloxy, trifluoroacetyl, imidazol-1-yl, acetamido,methylsulfamido, 2-oxooxazolidin-3-yl, 2-hydroxyethylamino, andmethylcarbamoyl;n is 0-3;wherein Ar excludes substituted or unsubstituted indazol-3-yl andsubstituted or unsubstituted 1H-pyrazolo[3,4-b]pyridyl;with the following proviso:proviso IVa: when R₁₀ is hydroxyl or carbamoyl, Ar cannot be phenyl,4-methyl-phenyl, 4-methoxy-phenyl, 4-halo-phenyl, or thiophen-yl when nis 0 or 1.

In a further aspect of the invention of formula IV, Ar is selected fromthe group consisting of phenyl, substituted phenyl, thiophen-yl,substituted thiophen-yl, pyridinyl, substituted pyridinyl, thiazolyl,and substituted thiazolyl.

In yet a further aspect of the invention of formula IV, Ar is selectedfrom phenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-chloro-2-methoxyphenyl,2-methoxy-4-(2-methyl-1H-imidazol-1-yl)phenyl, 1H-imidazol-1-yl-phenyl,2-methyl-1H-imidazol-1-yl-phenyl, 1H-imidazol-1-yl-thiophen-2-yl, and2-methyl-1H-imidazol-1-yl-thiophen-2-yl.

In a further aspect of the invention of formula IV, Ar is selected fromthe group consisting of aryl, substituted aryl, heteroaryl andsubstituted heteroaryl;

R₁ is selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₃-C₆cycloalkyl, aryl, substituted aryl, heteroaryl, and substitutedheteroaryl;R₁₀ is hydroxyl, carbamoyl, ureido, sulfamoylamino, 2-amino-2-oxoethyl,acetyl, hydroxyethyl, pyridin-3-ylamino, pyridin-4-ylamino,1-methylpyrrolidin-3-yloxy, trifluoroacetyl, imidazol-1-yl, acetamido,methylsulfamido, 2-oxooxazolidin-3-yl, 2-hydroxyethylamino, andmethylcarbamoyl;n is 0-3;with the following provisos:proviso IVa: Ar excludes substituted or unsubstituted indazol-3-yl andsubstituted or unsubstituted 1H-pyrazolo[3,4-b]pyridyl; andproviso IVb: when R₁₀ is hydroxyl or carbamoyl, Ar cannot be phenyl,4-methyl-phenyl, 4-methoxy-phenyl, 4-halo-phenyl, or thiophen-yl when nis 0 or 1.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom in thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible, but only if such combinations result in stable compounds.

The compounds described herein may have asymmetric centers. Compounds ofthe present invention containing an asymmetrically substituted atom maybe isolated in optically active or racemic forms. It is well known inthe art how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis from optically active starting materials.Many geometric isomers of olefins, C═N double bonds, and the like canalso be present in the compounds described herein, and all such stableisomers are contemplated in the present invention. Cis and transgeometric isomers of the compounds of the present invention aredescribed and may be isolated as a mixture of isomers or as separatedisomeric forms. All chiral, diastereomeric, racemic, and geometricisomeric forms of a structure are intended, unless the specificstereochemistry or isomeric form is specifically indicated. Alltautomers of shown or described compounds are also considered to be partof the present invention.

It is to be understood that isomers arising from such asymmetry (e.g.,all enantiomers and diastereomers) are included within the scope of theinvention, unless indicated otherwise. Such isomers can be obtained insubstantially pure form by classical separation techniques and bystereochemically controlled synthesis. Furthermore, the structures andother compounds and moieties discussed in this application also includeall tautomers thereof. Alkenes can include either the E- or Z-geometry,where appropriate.

2. Representative GSNOR Inhibitors

Table 1 below lists representative novel pyrrole analogs of Formula Iuseful as GSNOR inhibitors of the invention. The synthetic methods thatcan be used to prepare each compound, identified in Table 1 (i.e. Scheme1, Scheme 2, etc.) are detailed below. In some cases, if the startingmaterial or intermediate of a scheme is not commercially available, thena corresponding method (called Method 1, Method 2, etc.) describes thesynthesis of that starting material or intermediate. Table 1 providesScheme number, defines starting materials shown in Schemes, and wherenecessary provides the method number which corresponds to synthesis ofan intermediate or starting material. Supporting mass spectrometry datafor each compound is also included in Table 1. GSNOR inhibitor activitywas determined by the assay described in Example 2 and IC₅₀ values wereobtained. GSNOR inhibitor compounds 1-198 of Table 1 had an IC₅₀ ofabout <100 μM. GSNOR inhibitor compounds 1-42, 69-71, 73-77, 79-81,84-86, 92-103, 105-108, 110, 112-118, 120, 123-142, 144-164, 166-168,170-172, 175-181, 183, 185-198 of Table 1 had an IC₅₀ of about less than5.0 μM. GSNOR inhibitor compounds 1-25, 69, 75-76, 80, 84-86, 92-94,96-99, 101-103, 105-106, 110, 112-116, 118, 120, 124-126, 128-131,133-137, 139-141, 144, 146, 149-150, 152, 154-157, 162-163, 166-168,170-172, 175-180, 186-192, 194, and 196-197 of Table 1 had an IC₅₀ ofabout less than 1.0 μM.

TABLE 1 Molec- Compound Chemical ular Mass Scheme #/ # Structure nameformula weight Spec Method #  1

3-(5-(4-(1H- imidazol-1- yl)phenyl)- 1-(4- carbamoyl-2- methylphenyl)-1H-pyrrol-2- yl)propanoic acid C24H22N4O3 414.5 415.1 Scheme 5, Ar1 =4-carbamoyl-2- methylphenyl, R = H  2

3-(5-(5-(1H- imidazol-1- yl)thiophen-2- yl)-1-(4- carbamoyl-2-methylphenyl)- 1H-pyrrol-2- yl)propanoic acid C22H20N4O3S 420.5 421.1Scheme 9b, Ar = 1H-imidazol-1-yl  3

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4-(2-methyl- 1H-imidazol-1-yl)phenyl)-1H- pyrrol-2- yl)propanoic acid C25H24N4O3 428.5 429.1 Scheme9a, Ar = 2- methyl-1H- imidazol-1-yl  4

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(thiazol-5-yl)- 1H-pyrrol-2-yl)propanoic acid C18H17N3O3S 355.4 356.1 Scheme 1, R2 = thiazol-5-yl,R1 = 4-carbamoyl- 2-methylphenyl  5

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4- hydroxyphenyl)- 1H-pyrrol-2-yl)propanoic acid C21H20N2O4 364.4 365.1 Scheme 1, R2 = 4-hydroxyphenyl, R1 = 4-carbamoyl- 2-methylphenyl  6

3-(5-(5- bromothiophen- 2-yl)-1-(4- carbamoyl-2- methylphenyl)-1H-pyrrol-2- yl)propanoic acid C19H17BrN2O3S 433.3 433,  435   Scheme 1,R2 = 5- bromothiophen-2-yl, R1 = 4-carbamoyl- 2-methylphenyl  7

3-(1-(4- carbamoyl-2,6- dimethyl- phenyl)-5-(4- methoxy- phenyl)-1H-pyrrol-2- yl)propanoic acid C23H24N2O4 392.4 393.1 Scheme 1, R2 = 4-methoxyphenyl, R1 = 4-carbamoyl- 2,6-dimethylphenyl  8

3-(5-(4-(1H- imidazol-1- yl)phenyl)-1-(4- hydroxy-2- methylphenyl)-1H-pyrrol-2- yl)propanoic acid C23H21N3O3 387.4 388.2 Scheme 5, Ar1 = 4-hydroxy-2- methylphenyl, R = H  9

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4- methoxy- phenyl)-1H-pyrrol-2- yl)propanoic acid C22H22N2O4 378.4 379.1 Scheme 1, R2 = 4-methoxyphenyl, R1 = 4-carbamoyl- 2-methylphenyl  10

3-(1-(4- carbamoyl-2- chlorophenyl)- 5-(4- methoxy- phenyl)-1H-pyrrol-2- yl)propanoic acid C21H19ClN2O4 398.8 398.9 Scheme 1, R2 = 4-methoxyphenyl, R1 = 4-carbamoyl- 2-chloro- phenyl/Method 1  11

3-(5-(4- aminophenyl)-1- (4-carbamoyl-2- methylphenyl)- 1H-pyrrol-2-yl)propanoic acid C21H21N3O3 363.4 364.1 Scheme 4, R1 = 4- carbamoyl-2-methylphenyl  12

3-(5-(4- bromophenyl)- 1-(4- carbamoyl-2- methylphenyl)- 1H-pyrrol-2-yl)propanoic acid C21H19BrN2O3 427.3  427.1, 429.1 Scheme 6, Ar2 = 4-bromophenyl  13

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4-(furan-3- yl)phenyl)-1H-pyrrol-2- yl)propanoic acid C25H22N2O4 414.5 415.1 Scheme 3, R3 =furan-3-yl, R1 = 4-carbamoyl- 2-methylphenyl  14

3-(5-(4- methoxy- phenyl)-1-(2- methyl-4- sulfamoyl- phenyl)-1H-pyrrol-2- yl)propanoic acid C21H22N2O5S 414.5 (M − H+)− 413.1 Scheme 1,R2 = 4- methoxyphenyl, R1 = 2-methyl-4- sulfamoylphenyl  15

3-(1-(4- carbamoyl-2- methylphenyl)- 5-phenyl-1H- pyrrol-2- yl)propanoicacid C21H20N2O3 348.4 349.2 Scheme 1, R2 = phenyl, R1 = 4-carbamoyl-2-methylphenyl  16

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(3-chloro-4- methoxy- phenyl)-1H-pyrrol-2- yl)propanoic acid C22H21ClN2O4 412.9 413.1 Scheme 6, Ar2 = 3-chloro-4- methoxyphenyl  17

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(3-fluoro-4- methoxy- phenyl)-1H-pyrrol-2- yl)propanoic acid C22H21FN2O4 396.4 397.1 Scheme 6, Ar2 = 3-fluoro-4- methoxyphenyl  18

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4- cyanophenyl)- 1H-pyrrol-2-yl)propanoic acid C22H19N3O3 373.4 374.1 Scheme 1, R2 = 4- cyanophenyl,R1 = 4-carbamoyl- 2-methylphenyl  19

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(3-chloro-4- hydroxyphenyl)-1H-pyrrol-2- yl)propanoic acid C21H19ClN2O4 398.8 399.1 Scheme 1, R2 =3- chloro-4- hydroxyphenyl, R1 = 4-carbamoyl- 2-methylphenyl  20

3-(1-(4- carbamoyl-2- ethylphenyl)- 5-(4- methoxy- phenyl)-1H- pyrrol-2-yl)propanoic acid C23H24N2O4 392.4 393.1 Scheme 1, R2 = 4-methoxyphenyl, R1 = 4-carbamoyl- 2-ethylphenyl  21

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4-methoxy-3- methylphenyl)-1H-pyrrol-2- yl)propanoic acid C23H24N2O4 392.4 393.2 Scheme 6, Ar2 = 4-methoxy-3- methylphenyl  22

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4- iodophenyl)- 1H-pyrrol-2-yl)propanoic acid C21H19IN2O3 474.3 475.0 Scheme 1, R2 = 4- iodophenyl,R1 = 4- carbamoyl-2- methylphenyl  23

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(3- methoxy- phenyl)-1H-pyrrol-2- yl)propanoic acid C22H22N2O4 378.4 379.1 Scheme 1, R2 = 3-methoxyphenyl, R1 = 4-carbamoyl- 2-methylphenyl  24

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(6- methoxypyridin-3-yl)-1H-pyrrol- 2-yl)propanoic acid C21H21N3O4 379.4 380.1 Scheme 2, R2= 6- methoxypyridin-3- yl, R1 = 4- carbamoyl-2- methylphenyl  25

3-(5- (benzo[d] thiazol-6-yl)-1- (4-carbamoyl-2- methylphenyl)-1H-pyrrol-2- yl)propanoic acid C22H19N3O3S 405.5 406.1 Scheme 19, Ar2 =benzo[d]thiazol- 6-yl  26

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4- (methylthio) phenyl)-1H-pyrrol-2- yl)propanoic acid C22H22N2O3S 394.5 395.1 Scheme 6, Ar2 = 4-(methylthio)phenyl  27

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4- nitrophenyl)- 1H-pyrrol-2-yl)propanoic acid C21H19N3O5 393.4 394.1 Scheme 1, R2 = 4- nitrophenyl,R1 = 4-carbamoyl-2- methylphenyl  28

3-(5-(4-(1H- imidazol-1-yl)- phenyl)-1-(4- amino-2- methylphenyl)-1H-pyrrol-2- yl)propanoic acid C23H22N4O2 386.4 387.2 Scheme 20, (Step1, compound 20B, Ar2 = 4-(1H- imidazol-1- yl)phenyl), where 20A iscompound # 1 in this table  29

3-(5-(4-(4H- 1,2,4-triazol-4- yl)phenyl)-1-(4- carbamoyl-2-methylphenyl)- 1H-pyrrol-2- yl)propanoic acid C23H21N5O3 415.4 416.2Scheme 11  30

3-(5-(4-(2H- tetrazol-5- yl)phenyl)-1-(4- carbamoyl-2- methylphenyl)-1H-pyrrol-2- yl)propanoic acid C22H20N6O3 416.4 417.1 Scheme 26, (26C) 31

3-(1-(4- methoxy-2- methylphenyl)- 5-(4- methoxy- phenyl)-1H- pyrrol-2-yl)propanoic acid C22H23NO4 365.4 366.1 Scheme 1, R2 = 4- methoxyphenyl,R1 = 4-methoxy- 2-methylphenyl  32

3-(5- (benzo[d][1,3] dioxol-5-yl)-1- (4-carbamoyl-2- methylphenyl)-1H-pyrrol-2- yl)propanoic acid C22H20N2O5 392.4 (M − H)− 391.0 Scheme 6,Ar2 = benzo[d] [1,3]dioxol-5-yl  33

3-(5-(4- bromophenyl)- 1-(4-hydroxy-2- methylphenyl)- 1H-pyrrol-2-yl)propanoic acid C20H18BrNO3 400.3  400.1, 402.1 Scheme 5 to 5C (Ar1 =4-hydroxy- 2-methylphenyl), followed by final step of Scheme 5  34

3-(5-(6-(1H- imidazol-1- yl)pyridin-3-yl)- 1-(4- carbamoyl-2-methylphenyl)- 1H-pyrrol-2- yl)propanoic acid C23H21N5O3 415.4 416.0Scheme 2, R2 = 6- 1H-imidazol-1- yl)pyridin-3-yl, R1 = 4-carbamoyl-2-methyl- phenyl/Method 2  35

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(5- carbamoyl- thiophen-2-yl)-1H-pyrrol-2- yl)propanoic acid C20H19N3O4S 397.4 398.0 Scheme 2, R2 = 5-carbamoyl- thiophen-2-yl, R1 = 4- carbamoyl-2- methylphenyl  36

3-(5-(4-(1H- pyrazol-4- yl)phenyl)-1-(4- carbamoyl-2- methylphenyl)-1H-pyrrol-2- yl)propanoic acid C24H22N4O3 414.5 415.1 Scheme 3, R8 = 1H-pyrazol-4-yl, R1 = 4-carbamoyl-2- methylphenyl  37

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4- (trifluoro- methoxy)phenyl)-1H- pyrrol-2- yl)propanoic acid C22H19H3N2O4 432.4 433.1 Scheme6, Ar2 = 4- (trifluoro- methoxy)phenyl  38

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4- carbamoy- lphenyl)-1H-pyrrol-2- yl)propanoic acid C22H21N3O4 391.4 (M − H+)− 390.1 Scheme 2,R2 = 4- carbamoyl-phenyl, R1 = 4-carbamoyl- 2-methylphenyl  39

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4- (trifluoromethyl) phenyl)-1H-pyrrol-2- yl)propanoic acid C22H19F3N2O3 416.4 417.0 Scheme 6, Ar2 =4-(trifluoromethyl) phenyl  40

3-(5-(4-(1H- 1,2,4-triazol-1- yl)phenyl)-1-(4- carbamoyl-2-methylphenyl)- 1H-pyrrol-2- yl)propanoic acid C23H21N5O3 415.4 416.1Scheme 9a, Ar = 1H-1,2,4- triazol-1-yl  41

3-(5-(4-(1H- pyrazol-1- yl)phenyl)-1-(4- carbamoyl-2- methylphenyl)-1H-pyrrol-2- yl)propanoic acid C24H22N4O3 414.5 415.1 Scheme 9a, Ar =1H-pyrazol-1-yl  42

3-(5-(4-(2- amino-2- oxoethoxy) phenyl)-1-(4- carbamoyl-2-methylphenyl)- 1H-pyrrol-2- yl)propanoic acid C23H23N3O5 421.4 422.1Scheme 7, R1 = 4- carbamoyl-2- methylphenyl  43

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4-(1-methyl- 1H-pyrazol-4-yl)phenyl)-1H- pyrrol-2- yl)propanoic acid C25H24N4O3 428.5 429.2 Scheme3, R8 = 1- methyl-1H-pyrazol- 4-yl, R1 = 4- carbamoyl-2- methylphenyl 44

3-(5-(4-(1H- tetrazol-1- yl)phenyl)-1-(4- carbamoyl-2- methylphenyl)-1H-pyrrol-2- yl)propanoic acid C22H20N6O3 416.4 417.0 Scheme 12  45

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4-(4-methyl- 1H-imidazol-1-yl)phenyl)-1H- pyrrol-2- yl)propanoic acid C25H24N4O3 428.5 429.1 Scheme9a, Ar = 4- methyl-1H- imidazol-1-yl  46

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4- ureidophenyl)- 1H-pyrrol-2-yl)propanoic acid C22H22N4O4 406.4 407.0 Scheme 13  47

4-(2- (benzo[d][1,3] dioxol-5-yl)- 5-(2- carboxyethyl)- 1H-pyrrol-1-yl)-3-methylbenzoic acid C22H19NO6 393.4 (M − H+)− 392.0 Scheme 21, Ar2 =benzo[d][1,3] dioxol-5-yl  48

3-(1-(4- amino-2- methylphenyl)- 5-(4- bromophenyl)- 1H-pyrrol-2-yl)propanoic acid C20H19BrN2O2 399.3  399.1, 401.1 Scheme 22  49

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4- morpholino- phenyl)-1H-pyrrol-2- yl)propanoic acid C25H27N3O4 433.5 434.1 Scheme 10, R =morpholino  50

4-(2-(4-(2H- tetrazol-5- yl)phenyl)-5-(2- carboxyethyl)-1H-pyrrol-1-yl)- 3-methyl- benzoic acid C22H19N5O4 417.4 418.1 Scheme26, (26D)  51

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4-(pyridin-4- yl)phenyl)-1H-pyrrol-2- yl)propanoic acid C26H23N3O3 425.5 426.1 Scheme 3, R8 =pyridin-4-yl, R1 = 4-carbamoyl- 2-methylphenyl  52

3-(5-(4-(1H- pyrrol-1- yl)phenyl)-1-(4- carbamoyl-2- methylphenyl)-1H-pyrrol-2- yl)propanoic acid C25H23N3O3 413.5 414.1 Scheme 9a, Ar =1H-pyrrol-1-yl  53

3-(1-(4- hydroxy-2,5- dimethyl- phenyl)-5-(4- methoxy- phenyl)-1H-pyrrol-2- yl)propanoic acid C22H23NO4 365.4 366.1 Scheme 1, R2 = 4-methoxyphenyl, R1 = 4-hydroxy-2,5- dimethylphenyl  54

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4- (methylsulfon- amido)phenyl)-1H-pyrrol-2- yl)propanoic acid C22H23N3O5S 441.5 442.1 Scheme 14  55

3-(5-(4-(1H- 1,2,3-triazol-1- yl)phenyl)-1-(4- carbamoyl-2-methylphenyl)- 1H-pyrrol-2- yl)propanoic acid C23H21N5O3 415.4 416.0Scheme 15  56

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(naphthalen-2- yl)-1H-pyrrol-2-yl)propanoic acid C25H22N2O3 398.5 399.0 Scheme 1, R2 = naphthalen-2-yl, R1 = 4- carbamoyl-2- methylphenyl  57

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(3′- carbamoyl- biphenyl-4-yl)-1H-pyrrol-2- yl)propanoic acid C28H25N3O4 467.5 468.1 Scheme 3, R8 = 3-carbamoylphenyl, R1 = 4-carbamoyl- 2-methylphenyl  58

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4-(6-oxo-1,6- dihydropyridin-3-yl)phenyl)- 1H-pyrrol-2- yl)propanoic acid C26H23N3O4 441.5 442.1Scheme 3, R8 = 6- oxo-1,6- dihydropyridin-3-yl, R1 = 4-carbamoyl-2-methylphenyl  59

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4-(3,5- dimethyl- isoxazol-4-yl)phenyl)-1H- pyrrol-2- yl)propanoic acid C26H25N3O4 443.5 444.1 Scheme3, R8 = 3,5- dimethyl-isoxazol- 4-yl, R1 = 4- carbamoyl-2- methylphenyl 60

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4-(pyridin-3- yl)phenyl)-1H-pyrrol-2- yl)propanoic acid C26H23N3O3 425.5 426.2 Scheme 3, R3 =pyridin-3-yl, R1 = 4-carbamoyl- 2-methylphenyl  61

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4- (carboxy- methoxy)phenyl)-1H- pyrrol-2- yl)propanoic acid C23H22N2O6 422.4 423.6 Scheme 16 62

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4-(2- hydroxy- acetamido)phenyl)-1H- pyrrol-2- yl)propanoic acid C23H23N3O5 421.4 422.0 Scheme 18 63

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4-(2- methoxy- acetamido)phenyl)-1H- pyrrol-2- yl)propanoic acid C24H25N3O5 435.5 436.2 Scheme 17 64

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4-sulfamoyl- phenyl)-1H-pyrrol-2- yl)propanoic acid C21H21N3O5S 427.5 428.1 Scheme 1, R2 = 4-sulfamoyl-phenyl, R1 = 4-carbamoyl- 2-methylphenyl  65

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4-(piperazin- 1-yl)phenyl)-1H-pyrrol-2- yl)propanoic acid C25H28N4O3 432.5 433.1 Scheme 8, R = 2-oxoimida-zolidin- 1-yl  66

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4-(2- oxoimida- zolidin-1-yl)phenyl)-1H- pyrrol-2- yl)propanoic acid C24H24N4O4 432.5 433.1 Scheme8, R = 2- oxoimida-zolidin- 1-yl  67

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4- ethoxyphenyl)- 1H-pyrrol-2-yl)propanoic acid C23H24N2O4 392.4 393.1 Scheme 6, Ar2 = 4-ethoxyphenyl 68

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4- (methylsulfinyl) phenyl)-1H-pyrrol-2- yl)propanoic acid C22H22N2O4S 410.5 411.1 Scheme 23  69

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4-(2-ethyl- 1H-imidazol-1-yl)phenyl)-1H- pyrrol-2- yl)propanoic acid C26H26N4O3 442.5 443.2 Scheme5, Ar1 = 4-carbamoyl-2- methylphenyl, R = ethyl  70

3-(5-(4-(1H- imidazol-1- yl)phenyl-1-(4- (amino- methyl)-2-methylphenyl)- 1H-pyrrol-2- yl)propanoic acid C24H24N4O2 400.5 401.1Scheme 30  71

3-(1-(4-(1H- imidazol-2- yl)-2- methylphenyl)- 5-(4-methoxy- phenyl)-1H-pyrrol-2- yl)propanoic acid C24H23N3O3 401.5 402.2 Scheme 25, Ar1 = 4-(1H-imidazol-2-yl)- 2-methylphenyl  72

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4-furan-2- yl)phenyl)-1H-pyrrol-2- yl)propanoic acid C25H22N2O4 414.5 415.2 Scheme 3, step 1, R8= furan-2-yl, R1 = 4-carbamoyl- 2-methylphenyl, followed by the finalstep of scheme 5  73

3-(1-(4- dimethyl- carbamoyl)-2- methylphenyl)- 5-(4-methoxy-phenyl)-1H- pyrrol-2- yl)propanoic acid C24H26N2O4 406.5 407.1 Scheme27, Y = CH3, X1 = X2 = CH3  74

3-(5-(4- methoxy- phenyl)-1-(2- methyl-4- (methyl- carbamoyl)phenyl)-1H- pyrrol-2- yl)propanoic acid C23H24N2O4 392.4 393.1 Scheme27, Y = CH3, X1 = CH3, X2 = H  75

3-(1-(4-(2- methoxyethyl- carbamoyl)-2- methylphenyl)- 5-(4-methoxy-phenyl)-1H- pyrrol-2- yl)propanoic acid C25H28N2O5 436.5 437.2 Scheme27, Y = CH3, X1 = (CH2)2OMe, X2 = H  76

3-(1-(4-(2- hydroxyethyl- carbamoyl)-2- methylphenyl)- 5-(4-methoxy-phenyl)-1H- pyrrol-2- yl)propanoic acid C24H26N2O5 422.5 423.1 Scheme27, Y = CH3, X1 = (CH2)2OH, X2 = H  77

3-(5-(4- methoxy- phenyl)-1-(2- methyl-4- (oxazol-2- yl)phenyl)-1H-pyrrol-2- yl)propanoic acid C24H22N2O4 402.4 403.0 Scheme 25, Ar1 =2-methyl-4- (oxazol-2-yl) phenyl/ Method 4  78

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4- (methylsulfonyl) phenyl)-1H-pyrrol-2- yl)propanoic acid C22H22N2O5S 426.5 427.0 Scheme 28  79

3-(1-(4- hydroxy-2- methylphenyl)- 5-(4-methoxy- phenyl)-1H- pyrrol-2-yl)propanoic acid C21H21NO4 351.4 352.1 Scheme 1, R2 = 4- methoxyphenyl,R1 = 4-hydroxy-2- methylphenyl  80

3-(1-(2- chloro-4- hydroxyphenyl)- 5-(4-methoxy- phenyl)-1H- pyrrol-2-yl)propanoic acid C20H18ClNO4 371.8 372.1 Scheme 1, R2 = 4-methoxyphenyl, R1 = 2-chloro-4- hydroxyphenyl  81

3-(1-(4- hydroxy-2,3- dimethyl- phenyl)-5-(4- methoxy- phenyl)-1H-pyrrol-2- yl)propanoic acid C22H23NO4 365.4 366.1 Scheme 1, R2 = 4-methoxyphenyl, R1 = 4-hydroxy- 2,3- dimethylphenyl  82

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4-(pyrrolidin- 1-yl)phenyl)-1H-pyrrol-2- yl)propanoic acid C25H27N3O3 417.5 418.2 Scheme 10, R =pyrrolidin-1-yl  83

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4-(piperidin- 1-yl)phenyl)-1H-pyrrol-2- yl)propanoic acid C26H29N3O3 431.5 432.2 Scheme 10, R =piperidin-1-yl  84

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4-(1-methyl- 1H-pyrazol-5-yl)phenyl)-1H- pyrrol-2- yl)propanoic acid C25H24N4O3 428.5 429.1 Scheme3 step 1, R8 = 1-methyl-1H- pyrazol-5-yl, R1 = 4-carbamoyl-2-methylphenyl  85

ethyl 3-(5-(4- (1H-imidazol-1- yl)phenyl)-1-(4- carbamoyl-2-methylphenyl)- 1H-pyrrol-2- yl)propanoate C26H26N4O3 442.5 443.7 Scheme5 (first 4 steps), Ar1 = 4- carbamoyl-2- methylphenyl, R = H  86

ethyl 3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4-(2-methyl-1H-imidazol-1- yl)phenyl)-1H- pyrrol-2- yl)propanoate C27H28N4O3 456.5457.2 Scheme 9a step 1, Ar = 2-methyl-1H- imidazol-1-yl  87

ethyl 3-(1-(4- carbamoyl-2- methylphenyl)- 5-(5-(2-methyl-1H-imidazol-1- yl)thiophen-2- yl)-1H-pyrrol-2- yl)propanoate C24H24N4O3S448.5 449.1 Scheme 9b step 1, Ar = 1H-imidazol- 1-yl  88

ethyl 3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4-(furan-3- yl)phenyl)-1H-pyrrol-2- yl)propanoate C27H26N2O4 442.5 443.2 Scheme 3 (step 1), R3 =furan-3-yl, R1 = 4-carbamoyl- 2-methylphenyl  89

ethyl 3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4- cyanophenyl)-1H-pyrrol-2- yl)propanoate C24H23N3O3 401.5 402.2 Scheme 1 (first threesteps), R2 = 4- cyanophenyl, R1 = 4-carbamoyl- 2-methylphenyl  90

ethyl 3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4-(furan-2- yl)phenyl)-1H-pyrrol-2- yl)propanoate C27H26N2O4 442.5 443.0 Scheme 3, step 1, R8 =furan-2-yl, R1 = 4-carbamoyl- 2-methylphenyl  91

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(2-methoxy- pyrimidin-5-yl)-1H-pyrrol-2- yl)propanoic acid C20H20N4O4 380.4 381.1 Scheme 6, Ar2 = 2-methoxypyrimidin- 5-yl/method # 11  92

3-(5-(4-(1H- imidazol-1- yl)phenyl)-1-(2- methyl-4- (methyl-sulfonamido) phenyl)-1H- pyrrol-2- yl)propanoic acid C24H24N4O4S 464.5465.0 Scheme 20, Ar2 = 4- (1H-imidazol-1- yl)phenyl/where 20A iscompound # 1 in this table  93

3-(5-(4-(1H- imidazol-1- yl)phenyl)-1-(4- acetamido-2- methylphenyl)-1H-pyrrol-2- yl)propanoic acid C25H24N4O3 428.5 429.2 Scheme 31, whereacylating agent is acetic anhydride in glacial acetic acid at room temp,R1 = methyl.  94

3-(1-(4- hydroxy-2- (trifluoromethyl) phenyl)-5-(4- methoxy- phenyl)-1H-pyrrol-2- yl)propanoic acid C21H18F3NO4 405.4 406.0 Scheme 1 (firstthree steps), R2 = 4-methoxyphenyl, R1 = 4- hydroxyphenyl, R1 =4-hydroxy-2- (trifluoromethyl) phenyl, then Scheme5, 5D -> 5E  95

3-(5-(4- methoxy- phenyl)-1-(4- ((tetrahydro- furan-2- yl)methoxy)-2-(trifluoromethyl) phenyl)-1H- pyrrol-2- yl)propanoic acid C26H26F3NO5489.5 489.9 Scheme 1 (first three steps), R2 = 4-methoxyphenyl, R1 =4-((tetrahydro- furan-2- yl)methoxy)-2- (trifluoromethyl) phenyl, thenScheme 5, 5D -> 5E  96

3-(1-(4- carbamoyl-2- (trifluoromethyl) phenyl)-5-(4- methoxy-phenyl)-1H- pyrrol-2- yl)propanoic acid C22H19F3N2O4 432.4 432.8 Scheme27, Y = CF3, X1 = X2 = H, where the amine in step 2 is NH4OAc  97

3-(5-(4-(1H- imidazol-1- yl)phenyl)-1-(2- methyl-4- propionamido-phenyl)-1H- pyrrol-2- yl)propanoic acid C26H26N4O3 442.5 443.0 Scheme31, R1 = ethyl  98

3-(5-(4-(1H- imidazol-1- yl)phenyl)-1-(4- (2-methoxy- acetamido)-2-methylphenyl)- 1H-pyrrol-2- yl)propanoic acid C26H26N4O4 458.5 459.0Scheme 31, R1 = methoxy methyl  99

3-(5-(4-amino-3- chlorophenyl)-1- (4-carbamoyl-2- methylphenyl)-1H-pyrrol-2- yl)propanoic acid C21H20ClN3O3 397.9 398.0 Scheme 6, Ar2 =4-amino-3- chloro- phenyl/method 12 100

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(3,4- difluorophenyl)-1H-pyrrol-2- yl)propanoic acid C21H18F2N2O3 384.4 385.0 Scheme 6, Ar2 =3,4-difluorophenyl 101

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(2,4- difluorophenyl)-1H-pyrrol-2- yl)propanoic acid C21H18F2N2O3 384.4 385.0 Scheme 6, Ar2 =2,4- difluorophenyl 102

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4- chlorophenyl)- 1H-pyrrol-2-yl)propanoic acid C21H19ClN2O3 382.8 383.0 Scheme 6, Ar2 = 4-chlorophenyl 103

3-(5-(4- bromothiophen- 2-yl)-1-(4- carbamoyl-2- methylphenyl)-1H-pyrrol-2- yl)propanoic acid C19H17BrN2O3S 433.3  433.0, 434.8 Scheme1, R2 = 4-bromothiophen- 2-yl, R1 = 4- carbamoyl-2- methylphenyl 104

3-(5-(biphenyl- 4-yl)-1-(4- carbamoyl-2- methylphenyl)- 1H-pyrrol-2-yl)propanoic acid C27H24N2O3 424.5 425.1 Scheme 3, R8 = phenyl, R1 = 4-carbamoyl-2- methylphenyl 105

3-(1-(4- carbamoyl-2- fluorophenyl)-5- (4-methoxy- phenyl)-1H- pyrrol-2-yl)propanoic acid C21H19FN2O4 382.4 383.1 Scheme 1 (first three steps),R2 = 4-methoxyphenyl, R1 = 4-carbamoyl- 2-fluorophenyl, followed by laststep of Scheme 5 106

3-(5-(2-(1H- imidazol-1- yl)pyrimidin-5- yl)-1-(4- carbamoyl-2-methylphenyl)- 1H-pyrrol-2- yl)propanoic acid C22H20N6O3 416.4 417.0Scheme 42 107

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4-fluoro-3- methoxy- phenyl)-1H-pyrrol-2- yl)propanoic acid C22H21FN2O4 396.4 397.2 Scheme 6, Ar2 =4-fluoro-3- methoxyphenyl 108

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(3-cyano-4- fluorophenyl)-1H-pyrrol-2- yl)propanoic acid C22H18FN3O3 391.4 392.2 Scheme 6,1 Ar2 =3-cyano-4- fluorophenyl 109

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4- carbamoyl-3- fluorophenyl)-1H-pyrrol-2- yl)propanoic acid C22H20FN3O4 409.4 410.2 Scheme 6, Ar2 =4-carbamoyl-3- fluorophenyl 110

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4- methoxy-2- methylphenyl)-1H-pyrrol-2- yl)propanoic acid C23H24N2O4 392.4 393.2 Scheme 6, Ar2 =4-methoxy-2- methylphenyl 111

3-(5-(4- methoxy- phenyl)-1-(2- methyl-4- (thiazol-2- yl)phenyl)-1H-pyrrol-2- yl)propanoic acid C24H22N2O3S 418.5 419.0 Scheme 1, R2 =4-methoxyphenyl, R1 = 2-methyl-4- (thiazol-2- yl)phenyl, whereconversion of1 B to 1 C used μ-wave conditions described in prep. of29A/method 13 112

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4-chloro-2- fluorophenyl)-1H-pyrrol-2- yl)propanoic acid C21H18ClFN2O3 400.8 401.0 Scheme 6, Ar2 =4-chloro-2- fluorophenyl 113

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4- fluorophenyl)- 1H-pyrrol-2-yl)propanoic acid C21H19FN2O3 366.4 367.0 Scheme 6, Ar2 = 4-fluorophenyl114

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4-fluoro-2- methylphenyl)-1H-pyrrol-2- yl)propanoic acid C22H21FN2O3 380.4 381.1 Scheme 6, Ar2 =4-fluoro-2- methylphenyl 115

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4-chloro-2- (trifluoromethyl)phenyl)-1H- pyrrol-2- yl)propanoic acid C22H18ClF3N2O3 450.8 451.1Scheme 6, Ar2 = 4-chloro-2- (trifluoromethyl) phenyl 116

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4-chloro-2- methoxy- phenyl)-1H-pyrrol-2- yl)propanoic acid C22H21ClN2O4 412.9 413.0 Scheme 33, R1 =4-carbamoyl-2- methylphenyl, R2 = 4-chloro, R3 = methyl 117

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4-cyano-3- fluorophenyl)-1H-pyrrol-2- yl)propanoic acid C22H18FN3O3 391.4 392.0 Scheme 6, Ar2 =4-cyano-3- fluorophenyl 118

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(2-chloro-4- methoxy- phenyl)-1H-pyrrol-2- yl)propanoic acid C22H21ClN2O4 412.9 414.0 Scheme 6, Ar2 =2-chloro-4- methoxyphenyl 119

3-(1-(4-(2- (dimethylamino) ethyl- carbamoyl)-2- methylphenyl)-5-(4-methoxy- phenyl)-1H- pyrrol-2- yl)propanoic acid C26H31N3O4 449.5450.1 Scheme 27, Y = CF3, X1 = H, and X2 = NHCH2CH2N (CH3)2 120

3-(5-(4-(1H- imidazol-1- yl)thiophen-2- yl)-1-(4- carbamoyl-2-methylphenyl)- 1H-pyrrol-2- yl)propanoic acid C22H20N4O3S 420.5 421.1Scheme 9b, where SM is compound # 103 (before hydrolysis) instead of9b-A, Ar = 1H- imidazol-1-yl 121

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(3,5-dimethyl- 4-nitrophenyl)-1H-pyrrol-2- yl)propanoic acid C23H23N3O5 421.4 (M − H+)− 420.1 Scheme19, Ar2 = 3,5-dimethyl- 4-nitrophenyl 122

3-(5-(4-amino- 3,5-dimethyl- phenyl)-1-(4- carbamoyl-2- methylphenyl)-1H-pyrrol-2- yl)propanoic acid C23H25N3O3 391.5 392.2 Compound 121converted to Compound 122 following methodology described in Scheme 4123

3-(5-(2-(1H- imidazol-1- yl)thiazol-4-yl)- 1-(4-carbamoyl- 2-methyl-phenyl)-1H- pyrrol-2- yl)propanoic acid C21H19N5O3S 421.5 422.2 Scheme5, where starting ketone is 1-(2- bromothiazol-4- yl)ethanone, Ar1 = 4-carbamoyl-2- methylphenyl, R = H 124

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(2-ethoxy-4- fluorophenyl)-1H-pyrrol-2- yl)propanoic acid C23H23FN2O4 410.4 411.2 Scheme 6, Ar2 =2-ethoxy-4- fluorophenyl 125

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4-methoxy-2- (trifluoromethyl)phenyl)-1H- pyrrol-2- yl)propanoic acid C23H21F3N2O 446.4 447.2 Scheme6, Ar2 = 4-methoxy-2- (trifluoromethyl) phenyl 126

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4-fluoro-2- methoxy- phenyl)-1H-pyrrol-2- yl)propanoic acid C22H21FN2O4 396.4 397.1 Scheme 6, Ar2 =4-fluoro-2- methoxyphenyl 127

3-(5-(4- bromophenyl)- 1-(2-methyl-4- (pyridin-3- ylcarbamoyl)phenyl)-1H- pyrrol-2- yl)propanoic acid C26H22BrN3O3 504.4  504.1, 506.1Scheme 27, starting with 5B (from scheme 5) instead of 25C, Y = CH3, X1= H, and X2 = pyridin-3-yl 128

3-(5-(4- bromophenyl)- 1-(4-(6- methoxypyridin- 3-ylcarbamoyl)-2-methyl- phenyl)- 1H-pyrrol-2- yl)propanoic acid C27H24BrN3O 534.4534.0 Scheme 27, starting with 5B (from scheme 5) instead of 25C, Y =CH3, X1 = H, and X2 = 6- methoxypyridin- 3-yl 129

3-(5-(4- methoxy- phenyl)-1-(4- (6-methoxy- pyridin-3- ylcarbamoyl)-2-methyl- phenyl)-1H- pyrrol-2- yl)propanoic acid C28H27N3O5 485.5 486.0Scheme 27, Y = CH3, X1 = H, and X2 = 6- methoxypyridin- 3-yl 130

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4-(thiazol-5- yl)phenyl-1H-pyrrol-2- yl)propanoic acid C24H21N3O3S 431.5 432.2 Scheme 41 131

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4-chloro-3- fluorophenyl)-1H-pyrrol-2- yl)propanoic acid C21H18ClFN2O3 400.8 401.1 Scheme 6, Ar2 =4-chloro-3- fluorophenyl 132

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4-(hydroxy- carbamoyl)phenyl)-1H- pyrrol-2- yl)propanoic acid C22H21N3O5 407.4 408.0 Scheme35, compound 35-7 133

3-(5-(4- bromophenyl)- 1-(2-methyl-4- (pyridin-4- ylcarbamoyl)phenyl)-1H- pyrrol-2- yl)propanoic acid C26H22BrN3O3 504.4  504.2, 506.2Scheme 27, starting with 5B (from scheme 5) instead of 25C, Y = CH3, X1= H, and X2 = pyridin-4-yl 134

3-(5-(4- methoxy- phenyl)-1-(2- methyl-4- (pyridazin-4- ylcarbamoyl)phenyl)-1H- pyrrol-2- yl)propanoic acid C26H24N4O4 456.5 457.2 Scheme 32135

3-(5-(4- methoxy- phenyl)-1-(2- methyl-4- (pyridin-3- ylcarbamoyl)phenyl)-1H- pyrrol-2- yl)propanoic acid C27H25N3O4 455.5 456.2 Scheme27, Y = CH3, X1 = H, and X2 = pyridin-3-yl 136

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(5-(2-methyl- 1H-imidazol-1-yl)thiophen-2- yl)-1H-pyrrol-2- yl)propanoic acid C23H22N4O3S 434.5435.0 Scheme 9b, Ar = 2-methyl-1H- imidazol-1-yl 137

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(3-fluoro-4- (1H-imidazol-1-yl)phenyl)-1H- pyrrol-2- yl)propanoic acid C24H21FN4O3 432.4 433.1Scheme 36, R1 = 4-carbamoyl-2- methylphenyl, where 1st step was preparedaccording to Scheme 36A, R = H 138

3-(5-(4- methoxy- phenyl)-1-(2- methyl-4- (pyrimidin-5- ylcarbamoyl)phenyl)-1H- pyrrol-2- yl)propanoic acid C26H24N4O4 456.5 457.2 Scheme32, where amine is pyrimidin-5- amine instead of 32B 139

3-(5-(4-(2- methyl-1H- imidazol-1- yl)phenyl)-1-(2- methyl-4- (methyl-sulfonamido) phenyl)-1H- pyrrol-2- yl)propanoic acid C25H26N4O4S 478.6479.2 Scheme 20, Ar2 = 4-(2-methyl-1H- imidazol-1- yl)phenyl/where 20Ais compound # 3 in this table 140

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(3-fluoro-4-(2- methyl-1H-imidazol-1- yl)phenyl)-1H- pyrrol-2- yl)propanoic acid C25H23FN4O3 446.5447.1 Scheme 36, R1 = 4- carbamoyl-2- methylphenyl, where 1st step wasprepared according to Scheme 36A, R = Me 141

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4-chloro-2- ethoxyphenyl)-1H-pyrrol-2- yl)propanoic acid C23H23ClN2O4 426.9 427.1 Scheme 33, R1 =4-carbamoyl-2- methylphenyl, R2 = 4-chloro, R3 = ethyl 142

3-(5-(5-bromo- 2-methoxy- phenyl)-1-(4- carbamoyl-2- methylphenyl)-1H-pyrrol-2- yl)propanoic acid C22H21BrNO4 457.3 459.0 Scheme 33, R1 =4-carbamoyl-2- methylphenyl, R2 = 5-bromo, R3 = methyl 143

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4-(2- cyclopropyl-1H-imidazol-1- yl)phenyl)-1H- pyrrol-2- yl)propanoic acid C27H26N4O3 454.5455.0 Scheme 34, Ar1-X = 4- bromophenyl, Ar1 = phen-4-yl, Ar2 =2-cyclopropyl- 1H-imidazol-1- yl/Method 14 144

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4-(2-methyl- 1H-imidazol-1-yl)thiophen-2- yl)-1H-pyrrol-2- yl)propanoic acid C23H22N4O3S 434.5435.2 Scheme 9b, where SM was compound # 103 (before hydrolysis) insteadof 9b-A, Ar = 2- methyl-1H- imidazol-1-yl 145

3-(5-(4-bromo- 2-methoxy- phenyl)-1-(4- carbamoyl-2- methylphenyl)-1H-pyrrol-2- yl)propanoic acid C22H21BrN2O4 457.3 459.1 Scheme 1, R2 =4-bromo-2- methoxyphenyl, R1 = 4-carbamoyl- 2-methyl- phenyl/ Method 15146

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(2-methoxy-4- (2-methyl-1H-imidazol-1- yl)phenyl)-1H- pyrrol-2- yl)propanoic acid C26H26N4O4 458.5459.1 Scheme 34, Ar1-X = 4- bromo-2- methoxyphenyl, Ar2 = methyl-1H-imidazol-1-yl/ see previous compound for synthesis of 34A 147

3-(1-(4- acetamido-2- methylphenyl)- 5-(4- bromophenyl)- 1H-pyrrol-2-yl)propanoic acid C22H21BrN2O3 441.3  441.0, 442.9 Scheme 31, R1 =methyl (acetic anhydride as acylating agent), * methyl ester wasprepared (see asterik definition in scheme 31) 148

3-(5-(4- bromophenyl)- 1-(4-(2- methoxy- acetamido)-2- methylphenyl)-1H-pyrrol-2- yl)propanoic acid C23H23BrN2O4 471.3 4714.0,  472.9 Scheme31, R1 = methoxy methyl, * methyl ester was prepared (see asterikdefinition in scheme 31) 149

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4-chloro-2- hydroxy- phenyl)-1H-pyrrol-2- yl)propanoic acid C21H19ClN2O4 398.8 399.0 Scheme 1, R1 =4-carbamoyl-2- methylphenyl, R2 = 4-chloro- 2- hydroxyphenyl 150

3-(5-(5- bromothiophen- 3-yl)-1-(4- carbamoyl-2- methylphenyl)-1H-pyrrol-2- yl)propanoic acid C19H17BrN2O3S 433.3 434.9 Scheme 1, R2 =5-bromothiophen- 3-yl, R1 = 4-carbamoyl- 2-methyl- phenyl/ Method 19 151

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4-hydroxy-3- methylphenyl)-1H-pyrrol-2- yl)propanoic acid C22H22N2O4 378.4 379.1 Scheme 1, R2 =4-hydroxy-3- methylphenyl, R1 = 4-carbamoyl-2- methylphenyl 152

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(2-carbamoyl- 4-chlorophenyl)-1H-pyrrol-2- yl)propanoic acid C22H20ClN3O4 425.9 426.1 Scheme 6, Ar2 =2-carbamoyl-4- chlorophenyl, using 4-chloro-2- cyanophenyl- boronic acidin step 6E to 6F 153

3-(5-(2- acetamido-4- chlorophenyl)-1- (4-carbamoyl-2- methylphenyl)-1H-pyrrol-2- yl)propanoic acid C23H22ClN3O4 439.9 440.1 Scheme 40, R =CH3 154

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(2-methoxy- phenyl)-1H- pyrrol-2-yl)propanoic acid C22H22N2O4 378.4 379.1 Scheme 6, Ar2 = 2-methoxyphenyl155

4-(1-(4- carbamoyl-2- methylphenyl)- 5-(2- carboxyethyl)- 1H-pyrrol-2-yl)benzoic acid C22H20N2O5 392.4 393.1 Scheme 35, compound 35-5 156

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(2,4- dimethoxy- phenyl)-1H-pyrrol-2- yl)propanoic acid C23H24N2O5 408.4 409.2 Scheme 19, Ar2 = 2,4-dimethoxyphenyl 157

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4-chloro-2- propoxyphenyl)-1H-pyrrol-2- yl)propanoic acid C24H25ClN2O4 440.9 441.1 Scheme 33, R1 =4-carbamoyl-2- methylphenyl, R2 = 4-chloro, R3 = n-propyl 158

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4-chloro-2- (2-methoxy-acetamido) phenyl)-1H- pyrrol-2- yl)propanoic acid C24H24ClN3O5 469.9470.1 Scheme 40, R = methoxy methyl 159

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4-chloro-2- (methyl-sulfonamido) phenyl)-1H- pyrrol-2- yl)propanoic acid C22H22ClN3O5S 475.9476.0 Intermediate 16-4 (Method 16), then sulfonylated following 1ststep of Scheme 14, then final 2 steps of Scheme 6 160

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4-chloro-2- (methylamino)phenyl)-1H- pyrrol-2- yl)propanoic acid C22H22ClN3O3 411.9 412.1 Scheme39 (compound 39a-B) 161

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4-chloro-2- (methoxy-methyl)phenyl)- 1H-pyrrol-2- yl)propanoic acid C23H23ClN2O4 426.9 427.1Scheme 6, R2 = 4-chloro-2- (methoxymethyl) phenyl/Method 17 162

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4-hydroxy-2- methoxy-phenyl)-1H- pyrrol-2- yl)propanoic acid C22H22N2O5 394.4 395.1 Scheme 6,R2 = 4-hydroxy-2- methoxy- phenyl/Method 18 163

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4-chloro-2- (dimethylamino)phenyl)-1H- pyrrol-2- yl)propanoic acid C23H24ClN3O3 425.9 426.1 Scheme39 (compound 39b-B) 164

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4-(2- (hydroxy- methyl)-1H-imidazol-1- yl)phenyl)-1H- pyrrol-2- yl)propanoic acid C25H24N4O4 444.5445.1 Scheme 34, Ar1—X = 4- bromophenyl, Ar2 = 2- (hydroxymethyl)-1H-imidazol-1-yl, and R1 = 4- carbamoyl-2- methylphenyl/ Method 26 165

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4-(2- oxooxazolidin-3-yl)phenyl)- 1H-pyrrol-2- yl)propanoic acid C24H23N3O5 433.5 434.1Scheme 36, R1 = 2-oxooxazolidin- 3-yl, R2 = 4- carbamoyl-2-methylphenyl, and R3 = H 166

3-(5-(4-(1H- imidazol-1-yl)- 2-methoxy- phenyl)-1-(4- carbamoyl-2-methylphenyl)- 1H-pyrrol-2- yl)propanoic acid C25H24N4O4 444.5 445.2Scheme 36, R1 = 1H-imidazol-1-yl, R2 = 4-carbamoyl- 2-methylphenyl, andR3 = 2- methoxy/ method 15 167

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(5-(2-methyl- 1H-imidazol-1-yl)thiophen-3- yl)-1H-pyrrol-2- yl)propanoic acid C23H22N4O3S 434.5435.1 Scheme 34, Ar1—X = 5- bromothiophen- 3-yl, Ar2 = 2-methyl-1H-imidazol-1-yl, R1 = 4-carbamoyl- 2-methylphenyl 168

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(5- chlorothiophen-2-yl)-1H-pyrrol- 2-yl)propanoic acid C19H17ClN2O3S 388.9 389.0 Scheme 1,R2 = 5- chlorothiophen- 2-yl, R1 = 4- carbamoyl- 2-methylphenyl 169

3-(5-(5- bromothiazol-2- yl)-1-(4- carbamoyl-2- methylphenyl)-1H-pyrrol-2- yl)propanoic acid C18H16BrN3O3S 434.3 434.0 Scheme 1, R2 =5- bromothiazol-2-yl, R1 = 4-carbamoyl- 2-methylphenyl 170

3-(5-(4-(2- methyl-1H- imidazol-1- yl)thiophen-2- yl)-1-(2-methyl-4-(methyl- sulfonamido) phenyl)-1H- pyrrol-2- yl)propanoic acidC23H24N4O4S2 484.6 485.1 Scheme 34, Ar1—X = 4- bromothiophen- 2-yl, Ar2= 2-methyl- 1H-imidazol-1-yl, R1 = 2-methyl-4- (methyl- sulfonamido)phenyl 171

3-(5-(5-(2- methyl-1H- imidazol-1- yl)thiophen-2- yl)-1-(2-methyl-4-(methyl- sulfonamido) phenyl)-1H- pyrrol-2- yl)propanoic acidC23H24N4O4S2 484.6 485.0 Scheme 34, Ar1—X = 5- bromothiophen- 2-yl, Ar2= 2-methyl- 1H-imidazol-1-yl, R1 = 2-methyl-4- (methyl- sulfonamido)phenyl/ Method 23 172

3-(1-(4- acetamido-2- methylphenyl)- 5-(4-chloro-2- methoxy- phenyl)-1H-pyrrol-2- yl)propanoic acid C23H23ClN2O4 426.9 427.0 Scheme 33, R1 = 4-carbamoyl-2- methylphenyl, R2 = 4-chloro, R3 = methyl 173

3-(5-(4- bromothiazol- 2-yl)-1-(4- carbamoyl-2- methylphenyl)-1H-pyrrol-2- yl)propanoic acid C18H16BrN3O3S 434.3  434.1, 436.0 Scheme1, R1 = 4- carbamoyl-2- methylphenyl, R2 = 4- bromothiazol-2-yl/ method22 174

3-(5-(5- bromothiophen- 2-yl)-1-(2- methyl-4- (methyl- sulfonamido)phenyl)-1H- pyrrol-2- yl)propanoic acid C19H19BrN2O4S2 483.4 482.9Scheme 1, R1 = 2- methyl-4- (methyl- sulfonamido) phenyl, R2 = 5-bromothiophen-2- yl/method 23 175

3-(1-(4- acetamido-2- methylphenyl)- 5-(4-(2-methyl- 1H-imidazol-1-yl)phenyl)-1H- pyrrol-2- yl)propanoic acid C26H26N4O3 422.5 443.0Compound 3, then reduction according to Scheme 20 step 1, then acylationaccording to Scheme 31, R1 = methyl 176

3-(5-(4-chloro- 2-methoxy- phenyl)-1-(2- methyl-4- (methyl- sulfonamido)phenyl)-1H- pyrrol-2- yl)propanoic acid C22H23ClN2O5S 462.9 462.9 Scheme33, R1 = 2-methyl-4- (methyl- sulfonamido) phenyl, R2 = 4- chloro, R3 =methyl 177

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(5-(2-ethyl- 1H-imidazol-1-yl)thiophen-2- yl)-1H-pyrrol-2- yl)propanoic acid C24H24N4O3S 448.5449.1 Scheme 9b, Ar = 2-ethyl-1H- imidazol-1-yl 178

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4-chloro-2- formamido-phenyl)-1H- pyrrol-2- yl)propanoic acid C22H20ClN3O4 425.9 425.9 Scheme40, R = H, acylating agent is formic acid with Ac2O, 55° C., 10 min. 179

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(3- chlorothiophen-2-yl)-1H-pyrrol- 2-yl)propanoic acid C19H17ClN2O3S 388.9 389.0 Scheme 1,R1 = 4- carbamoyl-2- methylphenyl, R2 = 3- chlorothiophen-2- yl/method24 180

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4- formamido- 2-methoxy-phenyl)-1H- pyrrol-2- yl)propanoic acid C23H23N3O5 421.4 422.0 Scheme 6,4- formamido-2- methoxy- phenyl/Method 33 181

3-(5-(3-bromo- 5-methoxy- thiophen-2-yl)- 1-(4- carbamoyl- 2-methyl-phenyl)- 1H-pyrrol-2- yl)propanoic acid C20H19BrN2O4S 463.3 464.6 Scheme1, R1 = 4- carbamoyl-2- methylphenyl, R2 = 3-bromo-5- methoxythiophen-2-yl/method 25 182

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(5-(4- hydroxyphenyl)thiophen-2-yl)- 1H-pyrrol-2- yl)propanoic acid C25H22N2O4S 446.5 447.1see compound 6 before hydrolysis, then followed Scheme 6, step 6 with 4-hydroxyphenyl- boronic acid (see 6E to 6F), then last step of Scheme 6183

3-(5-(4- bromothiophen- 2-yl)-1-(2- methyl-4- (methyl- sulfonamido)phenyl)-1H- pyrrol-2- yl)propanoic acid C19H19BrN2O4S2 483.4 482.6Scheme 1, R1 = 2- methyl-4- (methyl- sulfonamido) phenyl, R2 = 4-bromothiophen-2- yl/method 23 (R = CH3) 184

2-(1-(4- carbamoyl-2- methylphenyl)- 5-(4-(thiophen- 3-yl)phenyl)-1H-pyrrol-2- yl)acetic acid C24H20N2O3S 416.5 416.8 Scheme 37 185

3-(5-(4- bromophenyl)- 1-(2- methyl-4- (methyl- sulfonamido) phenyl)-1H-pyrrol-2- yl)propanoic acid C21H21BrN2O4S 477.4 476.7 Scheme 1, R1 =2-methyl-4- (methyl- sulfonamido) phenyl, R2 = 4-bromophenyl/ method 23(R = CH3) 186

3-(5-(5-(1H- imidazol-1- yl)furan-2-yl)-1- (4-carbamoyl-2-methylphenyl)- 1H-pyrrol-2- yl)propanoic acid C22H20N4O4 404.4 404.9Scheme 34, Ar1—X = 5-bromofuran- 2-yl, Ar2 = 1H- imidazol-1-yl, R =4-carbamoyl- 2-methylphenyl/ (34A synthesis, see compound 193) 187

3-(5-(4-chloro- 2-methoxy- phenyl)-1-(2- methyl-4- sulfamoyl-phenyl)-1H- pyrrol-2- yl)propanoic acid C21H21ClN2O5S 448.9 449.0 Scheme1, R1 = 2-methyl-4- sulfamoylphenyl, R2 = 4-chloro-2- methoxyphenyl,Method 21 and Method 27 188

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4- chlorothiophen-2-yl)-1H-pyrrol- 2-yl)propanoic acid C19H17ClN2O3S 388.9 388.9 Scheme 1,R1 = 4- carbamoyl-2- methylphenyl, R2 = 4- chlorothiophen- 2-yl/Method28 (28-3) 189

3-(5-(5- bromo-4- chlorothiophen- 2-yl)-1-(4- carbamoyl-2-methylphenyl)- 1H-pyrrol-2- yl)propanoic acid C19H16BrClN2O3S 467.8 466.9, 468.8 Scheme 1, R1 = 4- carbamoyl-2- methylphenyl, R2 = 4-chlorothiophen- 2-yl/Method 28 (28-2) 190

3-(5-(4- bromothiophen- 2-yl)-1-(2- methyl-4- sulfamoyl- phenyl)-1H-pyrrol-2- yl)propanoic acid C18H17BrN2O4S2 469.4 470.9 Scheme 1, R1 = 2-methyl-4- (methyl- sulfonamido) phenyl, R2 = 4- bromothiophen-2-yl/method 27 191

3-(5-(4- methoxy- phenyl)-1-(2- methyl-4- (pyridin-4- ylcarbamoyl)phenyl)-1H- pyrrol-2- yl)propanoic acid C27H25N3O4 455.5 Scheme 43 192

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(5-(2-methyl- 1H-imidazol-1-yl)furan-2-yl)- 1H-pyrrol-2- yl)propanoic acid C23H22N4O4 418.4 419.1Scheme 34, Ar1—X = 5-bromofuran- 2-yl, Ar2 = 2- methyl-1H-imidazol-1-yl, R = 4-carbamoyl-2- methylphenyl/ (34A synthesis, seecompound 193) 193

3-(5-(5- bromofuran-2- yl)-1-(4- carbamoyl-2- methylphenyl)-1H-pyrrol-2- yl)propanoic acid C19H17BrN2O4 417.3 418.9 Scheme 38 194

3-(5-(5-methyl- 1H-imidazol-1- yl)thiophen-2- yl)-1-(2-methyl-4-sulfamoyl- phenyl)-1H- pyrrol-2- yl)propanoic acid C22H22N4O4S2 470.6471.0 Scheme 36, Ar1—Br = 5-bromo- thiophen-2-yl, Ar2 = 2-methyl-1H-imidazol-1-yl, R1 = 2-methyl-4- sulfamoyl- phenyl/Method 27 195

3-(5-(4- bromophenyl)- 1-(2-methyl-4- (sulfamoyl- amino)phenyl)-1H-pyrrol-2- yl)propanoic acid C20H20BrN3O4S 478.4 477.9 Scheme 1, R1 =2- methyl-4- (sulfamoylamino) phenyl, R2 = 4-bromo- phenyl/Method 29 196

3-(5-(4- methoxy- phenyl)-1-(2- methyl-4- (sulfamoyl- amino)phenyl)-1H-pyrrol-2- yl)propanoic acid C21H23N3O5S 429.5 430.0 Scheme 1, R1 = 2-methyl-4- (sulfamoylamino) phenyl, R2 = 4-methoxy- phenyl/Method 29 197

3-(5-(4-chloro- 2-methoxy- phenyl)-1-(2- methyl-4- (sulfamoyl-amino)phenyl)- 1H-pyrrol-2- yl)propanoic acid C21H22ClN3O5S 463.9 464.0Scheme 1, R1 = 2- methyl-4- (sulfamoylamino) phenyl, R2 = 4- chloro-2-methoxy- phenyl/Method 29 and Method 21 198

3-(1-(4- carbamoyl-2- methylphenyl)- 5-(4-methoxy- phenyl)-1H- pyrrol-2-yl)butanoic acid C23H24N2O4 392.4 393.2 Scheme 50

Table 2 below lists representative novel pyrrole analogs of Formula IIuseful as GSNOR inhibitors of the invention. The synthetic methods thatcan be used to prepare each compound, identified in Table 2 (i.e. Scheme1, Scheme 2, etc.) are detailed below. In some cases, if the startingmaterial or intermediate of a scheme is not commercially available, thena corresponding method (called Method 1, Method 2, etc.) describes thesynthesis of that starting material or intermediate. Table 2 providesScheme number, defines starting materials shown in Schemes, and wherenecessary provides the method number which corresponds to synthesis ofan intermediate or starting materials. Supporting mass spectrometry datafor each compound is also included in Table 2. GSNOR inhibitor activitywas determined by the assay described in Example 2 and IC₅₀ values wereobtained. GSNOR inhibitor compounds 199-236 of Table 2 had an IC₅₀ ofabout <100 μM. GSNOR inhibitor compounds 199-212, 216, 219, 221, 223,226, 229, 231, 232, 235, and 236 of Table 2 had an IC₅₀ of less than 5.0μM. GSNOR inhibitor compounds 199-202, 216, 219, 221, 231, and 235 ofTable 2 had an IC₅₀ of less than 1.0 μM.

TABLE 2 Molecular mass # Structure Compound name Formula weight specSynthesis 199

3-(5-(4- methoxyphenyl)-1-(1- oxoisoindolin-5-yl)- 1H-pyrrol-2-yl)propanoic acid C₂₂H₂₀N₂O₄ 376.4 377.1 Scheme 1A, R2 = 4-methoxyphenyl, R1 = 1-oxoisoindolin- 5-yl/Method 5 200

3-(1-(4-carbamoyl-3- methoxyphenyl)-5-(4- methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid C₂₂H₂₂N₂O₅ 394.4 395.1 Scheme 1, R2 = 4-methoxyphenyl, R1 = 4-carbamoyl-3- methoxyphenyl 201

3-(1-(1H- benzo[d]imidazol-6- yl)-5-(4- methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid C₂₁H₁₉N₃O₃ 361.4 362.1 Scheme 1, R2 = 4-methoxyphenyl, R1 = 1H- benzo[d]imidazol-6-yl 202

3-(1-(4-carbamoyl-3- hydroxyphenyl)-5-(4- methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid C₂₁H₂₀N₂O₅ 380.4 381.1 Scheme 1A, R2 = 4-methoxyphenyl, R1 = 4-carbamoyl-3- hydroxyphenyl 203

3-(1-(5- carbamoylpyridin-2- yl)-5-(4- methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid C₂₀H₁₉N₃O₄ 365.4 366.0 Scheme 1A, R2 = 4-methoxyphenyl, R1 = 5- carbamoylpyridin-2-yl 204

3-(1-(3-chloro-4- hydroxyphenyl)-5-(4- methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid C₂₀H₁₈ClNO₄ 371.8 372.1 Scheme 1A, R2 = 4-methoxyphenyl, R1 = 3-chloro-4- hydroxyphenyl 205

3-(1-(6- carbamoylpyridin-3- yl)-5-(4- methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid C₂₀H₁₉N₃O₄ 365.4 366.0 Scheme 1A, R2 = 4-methoxyphenyl, R1 = 6- carbamoylpyridin-3- yl/Method 6 206

3-(5-(4- methoxyphenyl)-1- (1-oxo-1,3- dihydroisobenzofuran-5-yl)-1H-pyrrol-2- yl)propanoic acid C₂₂H₁₉NO₅ 377.4 378.1 Scheme 1A, R2= 4- methoxyphenyl, R1 = 1-oxo-1,3- dihydroisobenzofuran- 5-yl 207

3-(1-(1H- benzo[d]midazol-6- yl)-5-phenyl-1H-pyrrol- 2-yl)propanoic acidC₂₀H₁₇N₃O₂ 331.4 332.1 Scheme 1, R2 = phenyl, R1 = 1H-benzo[d]imidazol-6-yl 208

3-(1-(1,3- dixoxisoindolin-5-yl)- 5-(4-methoxyphenyl)- 1H-pyrrol-2-yl)propanoic acid C₂₂H₁₈N₂O₅ 390.4 391.1 Scheme 1A, R2 = 4-methoxyphenyl, R1 = 1,3- dioxoisoindolin-5-yl 209

3-(1-(1H-indazol-5- yl)-5-(4- methoxyphenyl)-1H- pyrrol-2-yl)propanoicacid C₂₁H₁₉N₃O₃ 361.4 362.1 Scheme 1, R2 = 4- methoxyphenyl, R1 =1H-indazol-5-yl 210

3-(5-(4- methoxyphenyl)-1-(6- oxo-1,6- dihydropyridin-3-yl)-1H-pyrrol-2- yl)propanoic acid C₁₉H₁₈N₂O₄ 338.4 339.1 Scheme 1, R2 = 4-methoxyphenyl, R1 = 6-oxo-1,6- dihydropyridin-3-yl 211

3-(1-(2- aminobenzo[d]thiazol- 6-yl)-5-(4- methoxyphenyl)-1H-pyrrol-yl)propanoic acid C₂₁H₁₉N₃O₃S 393.5 394.0 Scheme 1A, R2 = 4-methoxyphenyl, R1 = 2- aminobenzo[d]thiazol- 6-yl/Method 7 212

3-(1-(4-hydroxy-3- methylphenyl)-5-(4- methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid C₂₁H₂₁NO₄ 351.4 352.1 Scheme 1A, R2 = 4-methoxyphenyl, R1 = 4-hydroxy-3- methylphenyl 213

3-(1-(1H-indazol-6-yl)- 5-(4-methoxyphenyl)- 1H-pyrrol-2- yl)propanoicacid C₂₁H₁₉N₃O₃ 361.4 362.1 Scheme 1, R2 = 4- methoxyphenyl, R1 =1H-indazol-6-yl 214

3-(1-(2-oxo-2,3- dihydro-1H- benzo[d]imidazol-5- yl)-5-phenyl-1H-pyrrol-2-yl)propanoic acid C₂₀H₁₇N₃O₃ 347.4 348.1 Scheme 1, R2 = phenyl,R1 = 2- oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl 215

3-(5-(4- methoxyphenyl)-1-(2- oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)- 1H-pyrrol-2- yl)propanoic acid C₂₁H₁₉N₃O₄ 377.4378.1 Scheme 1, R2 = 4- methoxyphenyl, R1 = 2-oxo-2,3- dihydro-1H-benzo[d]imidazol-5-yl 216

3-(5-(4- methoxyphenyl)-1- (quinolin-6-yl)-1H- pyrrol-2-yl)propanoicacid C₂₃H₂₀N₂O₃ 372.4 373.1 Scheme 25, Ar1 = quinolin-6-yl 217

3-(1-(4-hydroxy-3,5- dimethylphenyl)-5-(4- methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid C₂₂H₂₃NO₄ 365.4 366.1 Scheme 1, R2 = 4-methoxyphenyl, R1 = 4-hydroxy-3,5- dimethylphenyl 218

3-(5-(4-(1H-imidazol-1- yl)phenyl)-1-(5-(1H- imidazol-1-yl)pyridin-2-yl)-1H-pyrrol-2- yl)propanoic acid C₂₄H₂₀N₆O₂ 424.5 425.0 Scheme 29,R1 = 5- (1H-imidazol-1- yl)pyridin-2-yl) 219

3-(5-(4-(1H-imidazol- 1-yl)phenyl)-1-(5- methyl-1H-benzo[d]imidazol-6-yl)- 1H-pyrrol-2- yl)propanoic acid C₂₄H₂₁N₅O₂ 411.5412.0 Scheme 29, R1 = 5- methyl-1H- benzo[d]imidazol-6- yl/Method 30(30-3A) 220

3-(1-(3-chloro-4- cyanophenyl)-5-(4- methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid C₂₁H₁₇ClN₂O₃ 380.8 381.1 Scheme 1A, R1 = 3-chloro-4-cyanophenyl, R2 = 4- methoxyphenyl 221

3-(1-(4-carbamoyl-3- chlorophenyl)-5-(4- methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid C₂₁H₁₉ClN₂O₄ 398.8 399.1 Scheme 44 222

3-(1-(isoquinolin-6-yl)- 5-(4-methoxyphenyl)- 1H-pyrrol-2- yl)propanoicacid C₂₃H₂₀N₂O₃ 372.4 373.0 Scheme 36, steps 2 and 3, Ar2 = null, Ar1 =4- methoxyphenyl, R1 = isoquinolin-6- yl/Method 32 223

3-(1-(isoquinolin-7-yl)- 5-(4-methoxyphenyl)- 1H-pyrrol-2- yl)propanoicacid C₂₃H₂₀N₂O₃ 372.4 373.2 Scheme 36, steps 2 and 3, Ar2 = null, Ar1 =4- methoxyphenyl, R1 = isoquinolin-6- yl/Method 31 224

3-(1-(1H-indol-5-yl)-5- (4-methoxyphenyl)-1H- pyrrol-2-yl)propanoic acidC₂₂H₂₀N₂O₃ 360.4 361.5 Scheme 1A, R2 = 4- methoxyphenyl, R1 =1H-indol-5-yl 225

3-(1-(2-oxoindolin-5- yl)-5-phenyl-1H- pyrrol-2-yl)propanoic acidC₂₁H₁₈N₂O₃ 346.4 347.1 Scheme 1A, R2 = phenyl, R1 = 2- oxoindolin-5-yl226

3-(1-(3-cyano-4- fluorophenyl)-5-(4- methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid C₂₁H₁₇FN₂O₃ 364.4 363.1 (M − H)− Scheme 1A,R2 = 4- methoxyphenyl, R1 = 3-cyano-4- fluorophenyl 227

3-(1-(4-hydroxy-3- (methoxycarbonyl) phenyl)-5-phenyl-1H-pyrrol-2-yl)propanoic acid C₂₁H₁₉NO₅ 365.4 366.1 Scheme 45, R2 = H, R1 =4-hydroxy-3- (methoxycarbonyl) phenyl 228

3-(1-(4-hydroxy-3- (methoxycarbonyl) phenyl)-5-(4- methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid C₂₂H₂₁NO₆ 395.4 396.1 Scheme 45, R2 = OMe, R1= 4- hydroxy-3- (methoxycarbonyl) phenyl 229

3-(1-(3-fluoro-4- hydroxyphenyl)-5-(4- methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid C₂₀H₁₈FNO₄ 355.4 356.1 Scheme 45, R2 = OMe,R1 = 3- fluoro-4- hydroxyphenyl 230

3-(1-(4-hydroxy-3- (hydroxymethyl) phenyl)-5-phenyl-1H-pyrrol-2-yl)propanoic acid C₂₀H₁₉NO₄ 337.4 337.8 Scheme 46 231

3-(1-(3- aminobenzo[d]isoxazol- 6-yl)-5-(4- methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid C₂₁H₁₉N₃O₄ 377.4 377.7 Scheme 47 232

5-(2-(2-carboxyethyl)- 5-phenyl-1H-pyrrol-1- yl)-2-hydroxybenzoic acidC₂₀H₁₇NO₅ 351.4 352.1 Hydrolysis of compound 227 following proceduredescribed in final step of Scheme 1 233

3-(1-(3- aminobenzo[d]isoxazol- 5-yl)-5-(4- methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid C₂₁H₁₉N₃O₄ 377.4 378.1 Compound 226 iscyclized following same procedure described in step 2 of Scheme 47, withpurification by prep TLC 234

3-(1-(4-hydroxy-3- (hydroxymethyl) phenyl)-5-(4- methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid C₂₁H₂₁NO₅ 367.4 368.1 Compound 228 is reducedfollowing the same procedure described in Scheme 46 235

3-(5-(4-(2-methyl-1H- imidazol-1-yl)phenyl)- 1-(2-oxo-2,3-dihydrobenzo[d]oxazol- 5-yl)-1H-pyrrol-2- yl)propanoic acid C₂₄H₂₀N₄O₄428.4 428.9 Scheme 36, Ar2 = 2- methyl-1H-imidazol- 1-yl, Ar1 =phen-4-yl, R1 = 2-oxo-2,3- dihydrobenzo[d] oxazol-6-yl/Method 39 236

3-(5-(4-(2-methyl-1H- imidazol-1-yl)phenyl)- 1-(2-oxo-2,3-dihydrobenzo[d]oxazol- 6-yl)-1H-pyrrol-2- yl)propanoic acid C₂₄H₂₀N₄O₄428.4 428.9 Scheme 36, Ar2 = 2- methyl-1H-imidazol- 1-yl, Ar1 =phen-4-yl, R1 = 2-oxo-2,3- dihydrobenzo[d] oxazol-6-yl/Method 40

Table 3 below lists representative novel pyrrole analogs of Formula IIIuseful as GSNOR inhibitors of the invention. The synthetic methods thatcan be used to prepare each compound, identified in Table 2 (i.e. Scheme1, Scheme 2, etc.) are detailed below. In some cases, if the startingmaterial or intermediate of a scheme is not commercially available, thena corresponding method (called Method 1, Method 2, etc.) describes thesynthesis of that starting material or intermediate. Table 3 providesScheme number, defines starting materials shown in Schemes, and wherenecessary provides the method number which corresponds to synthesis ofan intermediate or starting materials. Supporting mass spectrometry datafor each compound is also included in Table 3. GSNOR inhibitor activitywas determined by the assay described in Example 2 and IC₅₀ values wereobtained. GSNOR inhibitor compounds 237-242 of Table 3 had an IC₅₀ ofabout <100 μM. GSNOR inhibitor compounds 237 and 238 of Table 3 had anIC₅₀ of about less than 5.0 μM.

TABLE 3 Chemical Molecular Mass # STRUCTURE Name formula weight SpecSynthesis 237

3-(1-(5- carbamoylthiophen- 2-yl)-5-(4- methoxyphenyl)- 1H-pyrrol-2-yl)propanoic acid C19H18N2O4S 370.4 371.1 Scheme 1, R2 = 4-methoxyphenyl, R1 = 5- carbamoylthiophen- 2-yl, /Method 8 238

3-(1-(5- carbamoylthiazol-2- yl)-5-(4- methoxyphenyl)- 1H-pyrrol-2-yl)propanoic acid C18H17N3O4S 371.4 371.9 Scheme 1, R2 = 4-methoxyphenyl, R1 = 5- carbamoylthiazol-2- yl 239

3-(1-(5- carbamoylthiophen- 2-yl)-5-(4- methoxyphenyl)- 1H-pyrrol-2-yl)propanoic acid C19H18N2O4S 370.4 371.1 Scheme 1, R2 = 4-methoxyphenyl, R1 = 4- carbamoylthiophen- 2-yl 240

3-(1-(5- carbamoylthiophen- 3-yl)-5-(4- methoxyphenyl)- 1H-pyrrol-2-yl)propanoic acid C19H18N2O4S 370.4 371.1 Scheme 1, R2 = 4-methoxyphenyl, R1 = 5- carbamoylthiophen- 3-yl/Method 9 241

3-(1-(4-(2-amino-2- oxoethyl)thiazol-2- yl)-5-(4- methoxyphenyl)-1H-pyrrol-2- yl)propanoic acid C19H19N3O4S 385.4 386.1 Scheme 1, R2 = 4-methoxyphenyl, R1 = 2-amino-2- oxoethyl)thiazol-2- yl, /Method 10 242

3-(1-(4- carbamoylthiazol-2- yl)-5-(4- methoxyphenyl)- 1H-pyrrol-2-yl)propanoic acid C18H17N3O4S 371.4 372.1 Scheme 1, R2 = 4-methoxyphenyl, R1 = 4- carbamoylthiazol-2- yl

Table 4 below lists representative novel pyrrole analogs of Formula IVuseful as GSNOR inhibitors of the invention. The synthetic methods thatcan be used to prepare each compound, identified in Table 4 (i.e. Scheme1, Scheme 2, etc.) are detailed below. In some cases, if the startingmaterial or intermediate of a scheme is not commercially available, thena corresponding method (called Method 1, Method 2, etc.) describes thesynthesis of that starting material or intermediate. Table 4 providesScheme number, defines starting materials shown in Schemes, and wherenecessary provides the method number which corresponds to synthesis ofan intermediate or starting materials. Supporting mass spectrometry datafor each compound is also included in Table 4. GSNOR inhibitor activitywas determined by the assay described in Example 2 and IC₅₀ values wereobtained. GSNOR inhibitor compounds 243-273 of Table 4 had an IC₅₀ ofabout <100 μM. GSNOR inhibitor compounds 243-244, 248-249, 251-253, 255,262, 264-271, and 273 of Table 4 had an IC₅₀ of less than 5.0 μM. GSNORinhibitor compounds 249, 251-253, 255, 262, 264, 267, 269-270, and 273of Table 4 had an IC₅₀ of less than 1.0 μM.

TABLE 4 Molec- Chemical ular Mass # Structure Compound Name formulaweight Spec Synthesis 243

3-(1-(4-carbamoylphenyl)- 5-(3-methoxyphenyl)-1H- pyrrol-2-yl)propanoicacid C21H20N2O4 364.4 365.1 Scheme 1, R2 = 3- methoxyphenyl, R1 = 4-carbamoylphenyl 244

3-(5-phenyl-1-(4- ureidophenyl)-1H-pyrrol- 2-yl)propanoic acidC20H19N3O3 349.4 350.1 Scheme 1, R2 = phenyl, R1 = 4- ureidophenyl 245

3-(5-phenyl-1-(4- (sulfamoylamino)phenyl)- 1H-pyrrol-2-yl)propanoic acidC19H19N3O4S 385.4 386.1 Scheme 1, R2 = phenyl, R1 = 4- (sulfamoylamino)phenyl 246

3-(1-(4-(2-amino-2- oxoethyl)phenyl)-5- phenyl-1H-pyrrol-2- yl)propanoicacid C21H20N2O3 348.4 349.1 Scheme 1, R2 = phenyl, R1 = 4-(2-amino-2-oxoethyl)phenyl 247

3-(1-(4-(2-amino-2- oxoethyl)phenyl)-5-(4- methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid C22H22N2O4 378.4 379.1 Scheme 1, R2 = 4-methoxyphenyl, R1 = 4-(2-amino-2- oxoethyl)phenyl 248

3-(5-(4-methoxyphenyl)- 1-(4- (methylcarbamoyl) phenyl)-1H-pyrrol-2-yl)propanoic acid C22H22N2O4 378.4 379.1 Scheme 1A, R2 = 4-methoxyphenyl, R1 = 4- (methylcarbamoyl) phenyl 249

3-(1-(4-hydroxyphenyl)-5- (4-(2-methyl-1H- imidazol-1-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid C23H21N3O3 387.4 388.0 Scheme 5, Ar1 = 4-hydroxyphenyl, R = CH3 250

2-(1-(4-hydroxyphenyl)-5- (4-methoxyphenyl)-1H- pyrrol-2-yl)acetic acidC19H17NO4 323.3 324.1 Followed Scheme 37, R = methoxy, Steps 1-3,followed by step 3 of Scheme 1 with 4- aminophenol, then hydrolysis byScheme 5 step 5 251

3-(5-(4-(1H-imidazol-1- yl)phenyl)-1-(4- hydroxyphenyl)-1H-pyrrol-2-yl)propanoic acid C22H19N3O3 373.4 374.2 Scheme 5, Ar1 = 4-hydroxyphenyl, R = H 252

3-(5-(5-(1H-imidazol-1- yl)thiophen-2-yl)-1-(4- hydroxyphenyl)-1H-pyrrol-2-yl)propanoic acid C20H17N3O3S 379.4 379.9 1st 3 Steps of Scheme1, R1 = 4- hydroxyphenyl, R2 = 5- bromothiophen-2- yl, then Scheme 5,Steps 4 and 5 (Ar1 = 4- hydroxyphenyl, R = H) 253

3-(1-(4-acetylphenyl)-5- (4-methoxyphenyl)-1H- pyrrol-2-yl)propanoicacid C22H21NO4 363.4 364.1 Scheme 45, R2 = methoxy, R1 = 4-acetylphenyl254

3-(1-(4-(1- hydroxyethyl)phenyl)-5- phenyl-1H-pyrrol-2- yl)propanoicacid C21H21HO3 335.4 336.2 Reduction of compound 253 following synthesisdescribed in Scheme 46 with NaBH4 255

3-(1-(4-hydroxyphenyl)-5- (4-(2-methyl-1H- imidazol-1-yl)thiophen-2-yl)-1H-pyrrol-2- yl)propanoic acid C21H19N3O3S 393.5 394.2 1st 3 Stepsof Scheme 1, R1 = 4- hydroxyphenyl, R2 = 4- bromothiophen-2- yl, thenScheme 5, Steps 4 and 5 (Ar1 = 4- hydroxyphenyl, R = H) 256

3-(5-(4-methoxyphenyl)- 1-(4-(pyridin-3- ylamino)phenyl)-1H-pyrrol-2-yl)propanoic acid C25H23N3O3 413.5 414.2 Scheme 48, R =pyridin-3-yl 257

3-(5-(4-methoxyphenyl)- 1-(4-(1-methylpyrrolidin- 3-yloxy)phenyl)-1H-pyrrol-2-yl)propanoic acid C25H28N2O4 420.5 421.1 Scheme 25, Ar1 = 4-(1-methylpyrrolidin- 3-yloxy) phenyl/Method 37 258

3-(5-(4-methoxyphenyl)- 1-(4-(pyridin-4- ylamino)phenyl)-1H-pyrrol-2-yl)propanoic acid C25H23N3O3 413.5 414.0 Scheme 48, R =pyridin-4-yl 259

3-(5-phenyl-1-(4-(2,2,2- trifluoroacetyl)phenyl)-1H-pyrrol-2-yl)propanoic acid C21H16F3NO3 387.4 388.1 Scheme 45, R1 =2,2,2- trifluoroacetyl) phenyl, R2 = H 260

3-(5-(4-methoxyphenyl)- 1-(4-(2,2,2- trifluoroacetyl)phenyl)-1H-pyrrol-2-yl)propanoic acid C22H18F3NO4 417.4 417.7 Scheme 45, R1 =2,2,2- trifluoroacetyl) phenyl, R2 = methoxy 261

3-(1-(4-(1H-imidazol-1- yl)phenyl)-5-(4- methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid C23H21N3O3 387.4 388.2 Scheme 1 using 1Aconditions/R1 = 4- (1H-imidazol-1- yl)phenyl and R2 = 4- methoxyphenyl262

3-(5-(4-chloro-2- methoxyphenyl)-1-(4- hydroxyphenyl)-1H-pyrrol-2-yl)propanoic acid C20H18ClNO4 371.8 372.1 Scheme 33, R1 = 4-hydroxyphenyl, R2 = 4-chloro, R3 = methyl 263

3-(1-(4-acetamidophenyl)- 5-(4-chloro-2- methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid C22H21ClN2O4 412.9 413.1 Scheme 33, R1 = 4-acetamidophenyl, R2 = 4-chloro, R3 = methyl/Method 36 264

3-(1-(4-carbamoylphenyl)- 5-(4-chloro-2- methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid C21H19ClN2O4 398.8 399.0 Scheme 33, R1 = 4-carbamoylphenyl, R2 = 4-chloro, R3 = methyl 265

3-(5-(4-chloro-2- methoxyphenyl)-1-(4- (methoxyphenyl)-1-(4-(methylsulfonamido) phenyl)-1H-pyrrol-2- yl)propanoic acid C21H21ClN2O5S448.9 449.1 Scheme 33, R1 = 4- (methyl- sulfonamido) phenyl, R2 = 4-chloro, R3 = methyl/Method 23, R = H 266

3-(5-(4-(2-methyl-1H- imidazol-1-yl)phenyl)-1- (4-(2-oxooxazolidin-3-yl)phenyl)-1H-pyrrol-2- yl)propanoic acid C26H24N4O4 456.5 457.2 Scheme36 (36B conditions for Step 1) Ar1 = 4-phenyl, Ar2 = 2-methyl-1H-imidazol-1-yl and R1 = 4-(2- oxooxazolidin-3- yl)phenyl/Method 38 267

3-(5-(4-(2-methyl-1H- imidazol-1-yl)thiophen-2- yl)-1-(4-(methylsulfonamido) phenyl)-1H-pyrrol-2- yl)propanoic acid C22H22N4O4S2470.6 470.9 Scheme 34, Ar1—X = 4- bromothiophen-2- yl, Ar2 = 2-methyl-1H-imidazol-1-yl, R1 = 4- (methyl- sulfonamido) phenyl/Method 23 268

3-(1-(4-acetamidophenyl)- 5-(4-(2-methyl-1H- imidazol-1-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid C25H24N4O3 428.5 429.1 Scheme 29, R1 = 4-acetamidophenyl, R2 = methyl/Method 36 269

3-(5-(2-methoxy-4-(2- methyl-1H-imidazol-1- yl)phenyl)-1-(4-(methylsulfonamido) phenyl)-1H-pyrrol-2- yl)propanoic acid C25H26N4O5S494.6 495.1 Scheme 34, Ar1—X = 2-methoxy- 4-bromophenyl, Ar2 =2-methyl-1H- imidazol-1-yl, R1 = 4- (methyl- sulfonamido) phenyl/Method23 and Method 15 270

3-(1-(4-acetamidophenyl)- 5-(4-(2-methyl-1H- imidazol-1-yl)thiophen-2-yl)-1H-pyrrol-2- yl)propanoic acid C23H22N4O3S 434.5 435.1 Scheme 1steps 1-3 to prepare 1C (R1 = 4- acetamidophenyl, R2 = 4-bromothiophen-2- yl) followed by the last 2 steps of scheme 5, R = CH3271

3-(5-(4-(2-methyl-1H- imidazol-1-yl)phenyl)-1- (4-(methylsulfonamido)phenyl)-1H-pyrrol-2- yl)propanoic acid C24H24N4O4S 464.5 464.9 Scheme34, Ar1—X = 4- bromophenyl, Ar2 = 2-methyl-1H- imidazol-1-yl, R1 = 4-(methyl- sulfonamido) phenyl/Method 23 272

3-(1-(4-(2- hydroxyethylamino) phenyl)-5-(4-(2-methyl-1H-imidazol-1-yl)phenyl)- 1H-pyrrol-2-yl)propanoic acid C25H26N4O3 430.5431.2 Scheme 49 273

3-(1-(4-hydroxyphenyl)-5- (5-(2-methyl-1H- imidazol-1-yl)thiophen-2-yl)-1H-pyrrol-2- yl)propanoic acid C21H19N3O3S 393.5 394.0 Scheme 1steps 1-3 to prepare 1C (R1 = 4- hydroxyphenyl, R2 = 5- bromothiophen-2-yl) followed by the last 2 steps of scheme 5, R = CH3

D. Pharmaceutical Compositions Comprising a GSNOR Inhibitor

The invention encompasses pharmaceutical compositions comprising atleast one GSNOR inhibitor described herein and at least onepharmaceutically acceptable carrier. Suitable carriers are described in“Remington: The Science and Practice, Twentieth Edition,” published byLippincott Williams & Wilkins, which is incorporated herein byreference. Pharmaceutical compositions according to the invention mayalso comprise one or more non-GSNOR inhibitor active agents.

The pharmaceutical compositions of the invention can comprise novelGSNOR inhibitors described herein, the pharmaceutical compositions cancomprise known compounds which previously were not know to have GSNORinhibitor activity, or a combination thereof.

The GSNOR inhibitors can be utilized in any pharmaceutically acceptabledosage form, including but not limited to injectable dosage forms,liquid dispersions, gels, aerosols, ointments, creams, lyophilizedformulations, dry powders, tablets, capsules, controlled releaseformulations, fast melt formulations, delayed release formulations,extended release formulations, pulsatile release formulations, mixedimmediate release and controlled release formulations, etc.Specifically, the GSNOR inhibitors described herein can be formulated:(a) for administration selected from the group consisting of oral,pulmonary, intravenous, intra-arterial, intrathecal, intra-articular,rectal, ophthalmic, colonic, parenteral, intracisternal, intravaginal,intraperitoneal, local, buccal, nasal, and topical administration; (b)into a dosage form selected from the group consisting of liquiddispersions, gels, aerosols, ointments, creams, tablets, sachets andcapsules; (c) into a dosage form selected from the group consisting oflyophilized formulations, dry powders, fast melt formulations,controlled release formulations, delayed release formulations, extendedrelease formulations, pulsatile release formulations, and mixedimmediate release and controlled release formulations; or (d) anycombination thereof.

For respiratory infections, an inhalation formulation can be used toachieve high local concentrations. Formulations suitable for inhalationinclude dry powder or aerosolized or vaporized solutions, dispersions,or suspensions capable of being dispensed by an inhaler or nebulizerinto the endobronchial or nasal cavity of infected patients to treatupper and lower respiratory bacterial infections.

Solutions or suspensions used for parenteral, intradermal, orsubcutaneous application can comprise one or more of the followingcomponents: (1) a sterile diluent such as water for injection, salinesolution, fixed oils, polyethylene glycols, glycerine, propylene glycolor other synthetic solvents; (2) antibacterial agents such as benzylalcohol or methyl parabens; (3) antioxidants such as ascorbic acid orsodium bisulfite; (4) chelating agents such asethylenediaminetetraacetic acid; (5) buffers such as acetates, citratesor phosphates; and (5) agents for the adjustment of tonicity such assodium chloride or dextrose. The pH can be adjusted with acids or bases,such as hydrochloric acid or sodium hydroxide. A parenteral preparationcan be enclosed in ampoules, disposable syringes or multiple dose vialsmade of glass or plastic.

Pharmaceutical compositions suitable for injectable use may comprisesterile aqueous solutions (where water soluble) or dispersions andsterile powders for the extemporaneous preparation of sterile injectablesolutions or dispersion. For intravenous administration, suitablecarriers include physiological saline, bacteriostatic water, CremophorEL (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In allcases, the composition must be sterile and should be fluid to the extentthat easy syringability exists. The pharmaceutical composition should bestable under the conditions of manufacture and storage and should bepreserved against the contaminating action of microorganisms such asbacteria and fungi.

The carrier can be a solvent or dispersion medium comprising, forexample, water, ethanol, polyol (for example, glycerol, propyleneglycol, and liquid polyethylene glycol, and the like), and suitablemixtures thereof. The proper fluidity can be maintained, for example, bythe use of a coating such as lecithin, by the maintenance of therequired particle size in the case of dispersion and by the use ofsurfactants. Prevention of the action of microorganisms can be achievedby various antibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In manycases, it will be preferable to include isotonic agents, for example,sugars, polyalcohols such as mannitol or sorbitol, and inorganic saltssuch as sodium chloride in the composition. Prolonged absorption of theinjectable compositions can be brought about by including in thecomposition an agent which delays absorption, for example, aluminummonostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the activereagent (e.g., GSNOR inhibitor) in the required amount in an appropriatesolvent with one or a combination of ingredients enumerated above, asrequired, followed by filtered sterilization. Generally, dispersions areprepared by incorporating at least one GSNOR inhibitor into a sterilevehicle that contains a basic dispersion medium and any other requiredingredients. In the case of sterile powders for the preparation ofsterile injectable solutions, exemplary methods of preparation includevacuum drying and freeze-drying, both of which yield a powder of theGSNOR inhibitor plus any additional desired ingredient from a previouslysterile-filtered solution thereof.

Oral compositions generally include an inert diluent or an ediblecarrier. They can be enclosed, for example, in gelatin capsules orcompressed into tablets. For the purpose of oral therapeuticadministration, the GSNOR inhibitor can be incorporated with excipientsand used in the form of tablets, troches, or capsules. Oral compositionscan also be prepared using a fluid carrier for use as a mouthwash,wherein the compound in the fluid carrier is applied orally and swishedand expectorated or swallowed. Pharmaceutically compatible bindingagents, and/or adjuvant materials can be included as part of thecomposition.

For administration by inhalation, the compounds are delivered in theform of an aerosol spray from pressured container or dispenser thatcontains a suitable propellant, e.g., a gas such as carbon dioxide, anebulized liquid, a vaporized solution, or a dry powder from a suitabledevice. For transmucosal or transdermal administration, penetrantsappropriate to the barrier to be permeated are used in the formulation.Such penetrants are generally known in the art, and include, forexample, for transmucosal administration, detergents, bile salts, andfusidic acid derivatives. Transmucosal administration can beaccomplished through the use of nasal sprays or suppositories. Fortransdermal administration, the active reagents are formulated intoointments, salves, gels, or creams as generally known in the art. Thereagents can also be prepared in the form of suppositories (e.g., withconventional suppository bases such as cocoa butter and otherglycerides) or retention enemas for rectal delivery.

In one embodiment, the GSNOR inhibitors are prepared with carriers thatwill protect against rapid elimination from the body. For example, acontrolled release formulation can be used, including implants andmicroencapsulated delivery systems. Biodegradable, biocompatiblepolymers can be used, such as ethylene vinyl acetate, polyanhydrides,polyglycolic acid, collagen, polyorthoesters, and polylactic acid.Methods for preparation of such formulations will be apparent to thoseskilled in the art.

Liposomal suspensions (including liposomes targeted to infected cellswith monoclonal antibodies to viral antigens) can also be used aspharmaceutically acceptable carriers. These can be prepared according tomethods known to those skilled in the art, for example, as described inU.S. Pat. No. 4,522,811.

Additionally, suspensions of the GSNOR inhibitors may be prepared asappropriate oily injection suspensions. Suitable lipophilic solvents orvehicles include fatty oils, such as sesame oil, or synthetic fatty acidesters, such as ethyl oleate, triglycerides, or liposomes. Non-lipidpolycationic amino polymers may also be used for delivery. Optionally,the suspension may also include suitable stabilizers or agents toincrease the solubility of the compounds and allow for the preparationof highly concentrated solutions.

It is especially advantageous to formulate oral or parenteralcompositions in dosage unit form for ease of administration anduniformity of dosage. Dosage unit form as used herein refers tophysically discrete units suited as unitary dosages for the subject tobe treated; each unit containing a predetermined quantity of GSNORinhibitor calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier. The specificationfor the dosage unit forms of the invention are dictated by and directlydependent on the unique characteristics of the GSNOR inhibitor and theparticular therapeutic effect to be achieved, and the limitationsinherent in the art of compounding such an active agent for thetreatment of individuals.

Pharmaceutical compositions according to the invention comprising atleast one GSNOR inhibitor can comprise one or more pharmaceuticalexcipients. Examples of such excipients include, but are not limited tobinding agents, filling agents, lubricating agents, suspending agents,sweeteners, flavoring agents, preservatives, buffers, wetting agents,disintegrants, effervescent agents, and other excipients. Suchexcipients are known in the art. Exemplary excipients include: (1)binding agents which include various celluloses and cross-linkedpolyvinylpyrrolidone, microcrystalline cellulose, such as Avicel® PH101and Avicel® PH102, silicified microcrystalline cellulose (ProSolvSMCC™), gum tragacanth and gelatin; (2) filling agents such as variousstarches, lactose, lactose monohydrate, and lactose anhydrous; (3)disintegrating agents such as alginic acid, Primogel, corn starch,lightly crosslinked polyvinyl pyrrolidone, potato starch, maize starch,and modified starches, croscarmellose sodium, cross-povidone, sodiumstarch glycolate, and mixtures thereof; (4) lubricants, including agentsthat act on the flowability of a powder to be compressed, includemagnesium stearate, colloidal silicon dioxide, such as Aerosil® 200,talc, stearic acid, calcium stearate, and silica gel; (5) glidants suchas colloidal silicon dioxide; (6) preservatives, such as potassiumsorbate, methylparaben, propylparaben, benzoic acid and its salts, otheresters of parahydroxybenzoic acid such as butylparaben, alcohols such asethyl or benzyl alcohol, phenolic compounds such as phenol, orquaternary compounds such as benzalkonium chloride; (7) diluents such aspharmaceutically acceptable inert fillers, such as microcrystallinecellulose, lactose, dibasic calcium phosphate, saccharides, and/ormixtures of any of the foregoing; examples of diluents includemicrocrystalline cellulose, such as Avicel® PH101 and Avicel® PH102;lactose such as lactose monohydrate, lactose anhydrous, and Pharmatose®DCL21; dibasic calcium phosphate such as Emcompress®; mannitol; starch;sorbitol; sucrose; and glucose; (8) sweetening agents, including anynatural or artificial sweetener, such as sucrose, saccharin sucrose,xylitol, sodium saccharin, cyclamate, aspartame, and acesulfame; (9)flavoring agents, such as peppermint, methyl salicylate, orangeflavoring, Magnasweet® (trademark of MAFCO), bubble gum flavor, fruitflavors, and the like; and (10) effervescent agents, includingeffervescent couples such as an organic acid and a carbonate orbicarbonate. Suitable organic acids include, for example, citric,tartaric, malic, fumaric, adipic, succinic, and alginic acids andanhydrides and acid salts. Suitable carbonates and bicarbonates include,for example, sodium carbonate, sodium bicarbonate, potassium carbonate,potassium bicarbonate, magnesium carbonate, sodium glycine carbonate,L-lysine carbonate, and arginine carbonate. Alternatively, only thesodium bicarbonate component of the effervescent couple may be present.

E. Kits Comprising the Compositions of the Invention

The present invention also encompasses kits comprising the compositionsof the invention. Such kits can comprise, for example, (1) at least oneGSNOR inhibitor; and (2) at least one pharmaceutically acceptablecarrier, such as a solvent or solution. Additional kit components canoptionally include, for example: (1) any of the pharmaceuticallyacceptable excipients identified herein, such as stabilizers, buffers,etc., (2) at least one container, vial or similar apparatus for holdingand/or mixing the kit components; and (3) delivery apparatus, such as aninhaler, nebulizer, syringe, etc.

F. Methods of Preparing GSNOR Inhibitors

The GSNOR inhibitors of the invention can readily be synthesized usingknown synthetic methodologies or via a modification of known syntheticmethodologies. As would be readily recognized by a skilled artisan, themethodologies described below allow the synthesis of pyrroles having avariety of substituents. Exemplary synthetic methods are described inthe examples below.

According to one synthetic protocol, reaction of 2-furaldehyde with anappropriately substituted acetophenone followed by treatment with astrong acid gives the appropriately substituted 1,4,7-trione.Cyclization of the trione to the corresponding 1,2,5-trisubstitutedpyrrole is readily achieved by reacting the trione with a primary aminein the presence of p-toluenesulfonic acid. In one embodiment of thepresent invention, further derivatization of the phenyl ring at C5 ofthe pyrrole is readily achieved, for example, by various cross-couplingreactions. For example, synthesis of the trisubstituted pyrroles byreacting 1-(4-chlorophenyl)ethanone and 2-furaldehyde will give thetarget pyrrole with 4-chlorophenyl group at C5. The aryl chloride can bederivatized by reaction with a boronic acid under Suzuki couplingconditions. Such routine derivatization methodologies allow the rapidgeneration of compound libraries for in vitro GSNOR inhibition studies.A variety of additional methods are described in Example 1 of thisdocument.

If needed, further purification and separation of enantiomers anddiastereomers can be achieved by routine procedures known in the art.Thus, for example, the separation of enantiomers of a compound can beachieved by the use of chiral HPLC and related chromatographictechniques. Diastereomers can be similarly separated. In some instances,however, diastereomers can simply be separated physically, such as, forexample, by controlled precipitation or crystallization.

The process of the invention, when carried out as prescribed herein, canbe conveniently performed at temperatures that are routinely accessiblein the art. In one embodiment, the process is performed at a temperaturein the range of about 25° C. to about 110° C. In another embodiment, thetemperature is in the range of about 40° C. to about 100° C. In yetanother embodiment, the temperature is in the range of about 50° C. toabout 95° C.

Synthetic steps that require a base are carried out using any convenientorganic or inorganic base. Typically, the base is not nucleophilic.Thus, in one embodiment, the base is selected from carbonates,phosphates, hydroxides, alkoxides, salts of disilazanes, and tertiaryamines.

The process of the invention, when performed as described herein, can besubstantially complete after several minutes to after several hoursdepending upon the nature and quantity of reactants and reactiontemperature. The determination of when the reaction is substantiallycomplete can be conveniently evaluated by ordinary techniques known inthe art such as, for example, HPLC, LCMS, TLC, and ¹H NMR.

G. Method of Treatment

The invention encompasses methods of preventing or treating (e.g.,alleviating one or more symptoms of) medical conditions through use ofone or more of the disclosed compounds. The methods compriseadministering a therapeutically effective amount of a GSNOR inhibitor toa patient in need. The compositions of the invention can also be usedfor prophylactic therapy.

The GSNOR inhibitor used in the methods of treatment according to theinvention can be: (1) a novel GSNOR inhibitor described herein, or apharmaceutically acceptable salt thereof, a prodrug thereof, or ametabolite thereof; (2) a compound which was known prior to the presentinvention, but wherein it was not known that the compound is a GSNORinhibitor, or a pharmaceutically acceptable salt thereof, a prodrugthereof, or a metabolite thereof; or (3) a compound which was knownprior to the present invention, and wherein it was known that thecompound is a GSNOR inhibitor, but wherein it was not known that thecompound is useful for the methods of treatment described herein, or apharmaceutically acceptable salt thereof, a prodrug thereof, or ametabolite thereof.

The patient can be any animal, domestic, livestock or wild, including,but not limited to cats, dogs, horses, pigs and cattle, and preferablyhuman patients. As used herein, the terms patient and subject may beused interchangeably.

In subjects with deleteriously high levels of GSNOR or GSNOR activity,modulation may be achieved, for example, by administering one or more ofthe disclosed compounds that disrupts or down-regulates GSNOR function,or decreases GSNOR levels. These compounds may be administered withother GSNOR inhibitor agents, such as anti-GSNOR antibodies or antibodyfragments, GSNOR antisense, iRNA, or small molecules, or otherinhibitors, alone or in combination with other agents as described indetail herein.

The present invention provides a method of treating a subject afflictedwith a disorder ameliorated by NO donor therapy. Such a method comprisesadministering to a subject a therapeutically effective amount of a GSNORinhibitor.

As used herein, “treating” describes the management and care of apatient for the purpose of combating a disease, condition, or disorderand includes the administration of a compound of the present inventionto prevent the onset of the symptoms or complications, alleviating thesymptoms or complications, or eliminating the disease, condition ordisorder. More specifically, “treating” includes reversing, attenuating,alleviating, minimizing, suppressing or halting at least one deleterioussymptom or effect of a disease (disorder) state, disease progression,disease causative agent (e.g., bacteria or viruses), or other abnormalcondition. Treatment is continued as long as symptoms and/or pathologyameliorate.

The disorders can include pulmonary disorders associated with hypoxemiaand/or smooth muscle constriction in the lungs and/or lung infectionand/or lung injury (e.g., pulmonary hypertension, ARDS, asthma,pneumonia, pulmonary fibrosis/interstitial lung diseases, cysticfibrosis, COPD) cardiovascular disease and heart disease, includingconditions such as hypertension, ischemic coronary syndromes,atherosclerosis, heart failure, glaucoma, diseases characterized byangiogenesis (e.g., coronary artery disease), disorders where there isrisk of thrombosis occurring, disorders where there is risk ofrestenosis occurring, chronic inflammatory diseases (e.g., AID dementiaand psoriasis), diseases where there is risk of apoptosis occurring(e.g., heart failure, atherosclerosis, degenerative neurologicdisorders, arthritis and liver injury (ischemic or alcoholic)),impotence, obesity caused by eating in response to craving for food,stroke, reperfusion injury (e.g., traumatic muscle injury in heart orlung or crush injury), and disorders where preconditioning of heart orbrain for NO protection against subsequent ischemic events isbeneficial.

In one embodiment, the compounds of the present invention or apharmaceutically acceptable salt thereof, or a prodrug or metabolitethereof, can be administered in combination with an NO donor. An NOdonor donates nitric oxide or a related redox species and more generallyprovides nitric oxide bioactivity, that is activity which is identifiedwith nitric oxide, e.g., vasorelaxation or stimulation or inhibition ofa receptor protein, e.g., ras protein, adrenergic receptor, NFκB. NOdonors including S-nitroso, O-nitroso, C-nitroso and N-nitroso compoundsand nitro derivatives thereof and metal NO complexes, but not excludingother NO bioactivity generating compounds, useful herein are describedin “Methods in Nitric Oxide Research,” Feelisch et al. eds., pages71-115 (J. S., John Wiley & Sons, New York, 1996), which is incorporatedherein by reference. NO donors which are C-nitroso compounds wherenitroso is attached to a tertiary carbon which are useful herein includethose described in U.S. Pat. No. 6,359,182 and in WO 02/34705. Examplesof S-nitroso compounds, including S-nitrosothiols useful herein,include, for example, S-nitrosoglutathione,S-nitroso-N-acetylpenicillamine, S-nitroso-cysteine and ethyl esterthereof, S-nitroso cysteinyl glycine,S-nitroso-gamma-methyl-L-homocysteine, S-nitroso-L-homocysteine,S-nitroso-gamma-thio-L-leucine, S-nitroso-delta-thio-L-leucine, andS-nitrosoalbumin. Examples of other NO donors useful herein are sodiumnitroprusside (nipride), ethyl nitrite, isosorbide, nitroglycerin, SIN 1which is molsidomine, furoxamines, N-hydroxy (N-nitrosamine) andperfluorocarbons that have been saturated with NO or a hydrophobic NOdonor.

The combination of a GSNOR inhibitor with R(+) enantiomer of amlodipine,a known NO releaser (Zhang X. P at al. 2002 J. CardiovascularPharmacology 39, 208-214) is also an embodiment of the presentinvention.

The present invention also provides a method of treating a subjectafflicted with pathologically proliferating cells where the methodcomprises administering to said subject a therapeutically effectiveamount of an inhibitor of GSNOR. The inhibitors of GSNOR are thecompounds as defined above, or a pharmaceutically acceptable saltthereof, or a prodrug or metabolite thereof, in combination with apharmaceutically acceptable carrier. Treatment is continued as long assymptoms and/or pathology ameliorate.

In another embodiment, the pathologically proliferating cells can bepathologically proliferating microbes. The microbes involved can bethose where GSNOR is expressed to protect the microbe from nitrosativestress or where a host cell infected with the microbe expresses theenzyme, thereby protecting the microbe from nitrosative stress. The term“pathologically proliferating microbes” is used herein to meanpathologic microorganisms including but not limited to pathologicbacteria, pathologic viruses, pathologic Chlamydia, pathologic protozoa,pathologic Rickettsia, pathologic fungi, and pathologic mycoplasmata.More detail on the applicable microbes is set forth at columns 11 and 12of U.S. Pat. No. 6,057,367. The term “host cells infected withpathologic microbes” includes not only mammalian cells infected withpathologic viruses but also mammalian cells containing intracellularbacteria or protozoa, e.g., macrophages containing Mycobacteriumtuberculosis, Mycobacterium leper (leprosy), or Salmonella typhi(typhoid fever).

In another embodiment, the pathologically proliferating cells can bepathologic helminths. The term “pathologic helminths” is used herein torefer to pathologic nematodes, pathologic trematodes and pathologiccestodes. More detail on the applicable helminths is set forth at column12 of U.S. Pat. No. 6,057,367.

In another embodiment, the pathologically proliferating cells can bepathologically proliferating mammalian cells. The term “pathologicallyproliferating mammalian cells” as used herein means cells of the mammalthat grow in size or number in said mammal so as to cause a deleteriouseffect in the mammal or its organs. The term includes, for example, thepathologically proliferating or enlarging cells causing restenosis, thepathologically proliferating or enlarging cells causing benign prostatichypertrophy, the pathologically proliferating cells causing myocardialhypertrophy and proliferating cells at inflammatory sites such assynovial cells in arthritis or cells associated with a cellproliferation disorder.

As used herein, the term “cell proliferative disorder” refers toconditions in which the unregulated and/or abnormal growth of cells canlead to the development of an unwanted condition or disease, which canbe cancerous or non-cancerous, for example a psoriatic condition. Asused herein, the term “psoriatic condition” refers to disordersinvolving keratinocyte hyperproliferation, inflammatory cellinfiltration, and cytokine alteration. The cell proliferative disordercan be a precancerous condition or cancer. The cancer can be primarycancer or metastatic cancer, or both.

As used herein, the term “cancer” includes solid tumors, such as lung,breast, colon, ovarian, pancreas, prostate, adenocarcinoma, squamouscarcinoma, sarcoma, malignant glioma, leiomyosarcoma, hepatoma, head andneck cancer, malignant melanoma, non-melanoma skin cancers, as well ashematologic tumors and/or malignancies, such as leukemia, childhoodleukemia and lymphomas, multiple myeloma, Hodgkin's disease, lymphomasof lymphocytic and cutaneous origin, acute and chronic leukemia such asacute lymphoblastic, acute myelocytic or chronic myelocytic leukemia,plasma cell neoplasm, lymphoid neoplasm and cancers associated withAIDS.

In addition to psoriatic conditions, the types of proliferative diseaseswhich may be treated using the compositions of the present invention areepidermic and dermoid cysts, lipomas, adenomas, capillary and cutaneoushemangiomas, lymphangiomas, nevi lesions, teratomas, nephromas,myofibromatosis, osteoplastic tumors, and other dysplastic masses andthe like. In one embodiment, proliferative diseases include dysplasiasand disorders of the like.

In one embodiment, the treating cancer comprises a reduction in tumorsize, decrease in tumor number, a delay of tumor growth, decrease inmetastatic lesions in other tissues or organs distant from the primarytumor site, an improvement in the survival of patients, or animprovement in the quality of patient life, or at least two of theabove.

In another embodiment, the treating a cell proliferative disordercomprises a reduction in the rate of cellular proliferation, reductionin the proportion of proliferating cells, a decrease in size of an areaor zone of cellular proliferation, or a decrease in the number orproportion of cells having an abnormal appearance or morphology, or atleast two of the above.

In yet another embodiment, the compounds of the present invention or apharmaceutically acceptable salt thereof, a prodrug thereof, ormetabolite thereof, can be administered in combination with a secondchemotherapeutic agent. In a further embodiment, the secondchemotherapeutic agent is selected from the group consisting oftamoxifen, raloxifene, anastrozole, exemestane, letrozole, cisplatin,carboplatin, paclitaxel, cyclophosphamide, lovastatin, minosine,gemcitabine, ara C, 5-fluorouracil, methotrexate, docetaxel, goserelin,vincristine, vinblastin, nocodazole, teniposide, etoposide, epothilone,navelbine, camptothecin, daunonibicin, dactinomycin, mitoxantrone,amsacrine, doxorubicin, epirubicin, idarubicin imatanib, gefitinib,erlotinib, sorafenib, sunitinib malate, trastuzumab, rituximab,cetuximab, and bevacizumab.

In one embodiment, the compounds of the present invention or apharmaceutically acceptable salt thereof, a prodrug thereof, ormetabolite thereof, can be administered in combination with an agentthat imposes nitrosative or oxidative stress. Agents for selectivelyimposing nitrosative stress to inhibit proliferation of pathologicallyproliferating cells in combination therapy with GSNOR inhibitors hereinand dosages and routes of administration therefor include thosedisclosed in U.S. Pat. No. 6,057,367, which is incorporated herein.Supplemental agents for imposing oxidative stress (i.e., agents thatincrease GSSG (oxidized glutathione) over GSH (glutathione) ratio orNAD(P) over NAD(P)H ratio or increase thiobarbituric acid derivatives)in combination therapy with GS-FDH inhibitors herein include, forexample, L-buthionine-5-sulfoximine (BSO), glutathione reductaseinhibitors (e.g., BCNU), inhibitors or uncouplers of mitochondrialrespiration and drugs that increase reactive oxygen species (ROS), e.g.,adriamycin, in standard dosages with standard routes of administration.

GSNOR inhibitors may also be co-administered with a phosphodiesteraseinhibitor (e.g., rolipram, cilomilast, roflumilast, Viagra® (sildenafilcitrate), Cialis® (tadalafil), Levitra® (vardenafil), etc.) a β-agonist,a steroid, or a leukotriene antagonist (LTD4). Those skilled in the artcan readily determine the appropriate therapeutically effective amountdepending on the disorder to be ameliorated.

GSNOR inhibitors may be used as a means to improve β-adrenergicsignaling. In particular, inhibitors of GSNOR alone or in combinationwith β-agonists could be used to treat or protect against heart failure,or other vascular disorders such as hypertension and asthma. GSNORinhibitors can also be used to modulate G protein coupled receptors(GPCRs) by potentiating Gs G-protein, leading to smooth musclerelaxation (e.g., airway and blood vessels), and by attenuating GqG-protein, and thereby preventing smooth muscle contraction (e.g., inairway and blood vessels).

The therapeutically effective amount for the treatment of a subjectafflicted with a disorder ameliorated by NO donor therapy is the GSNORinhibiting amount in vivo that causes amelioration of the disorder beingtreated or protects against a risk associated with the disorder. Forexample, for asthma, a therapeutically effective amount is abronchodilating effective amount; for cystic fibrosis, a therapeuticallyeffective amount is an airway obstruction ameliorating effective amount;for ARDS, a therapeutically effective amount is a hypoxemia amelioratingeffective amount; for heart disease, a therapeutically effective amountis an angina relieving or angiogenesis inducing effective amount; forhypertension, a therapeutically effective amount is a blood pressurereducing effective amount; for ischemic coronary disorders, atherapeutic amount is a blood flow increasing effective amount; foratherosclerosis, a therapeutically effective amount is an endothelialdysfunction reversing effective amount; for glaucoma, a therapeuticamount is an intraocular pressure reducing effective amount; fordiseases characterized by angiogenesis, a therapeutically effectiveamount is an angiogenesis inhibiting effective amount; for disorderswhere there is risk of thrombosis occurring, a therapeutically effectiveamount is a thrombosis preventing effective amount; for disorders wherethere is risk of restenosis occurring, a therapeutically effectiveamount is a restenosis inhibiting effective amount; for chronicinflammatory diseases, a therapeutically effective amount is aninflammation reducing effective amount; for disorders where there isrisk of apoptosis occurring, a therapeutically effective amount is anapoptosis preventing effective amount; for impotence, a therapeuticallyeffective is an erection attaining or sustaining effective amount; forobesity, a therapeutically effective amount is a satiety causingeffective amount; for stroke, a therapeutically effective amount is ablood flow increasing or a TIA protecting effective amount; forreperfusion injury, a therapeutically effective amount is a functionincreasing effective amount; and for preconditioning of heart and brain,a therapeutically effective amount is a cell protective effectiveamount, e.g., as measured by triponin or CPK.

The therapeutically effective amount for the treatment of a subjectafflicted with pathologically proliferating cells means a GSNORinhibiting amount in vivo which is an antiproliferative effectiveamount. Such antiproliferative effective amount as used herein means anamount causing reduction in rate of proliferation of at least about 20%,at least about 10%, at least about 5%, or at least about 1%.

In general, the dosage, i.e., the therapeutically effective amount,ranges from 1 μg to 10 g/kg and often ranges from 10 μg to 1 g/kg or 10μg to 100 mg/kg body weight of the subject being treated, per day.

H. Other Uses

The compounds of the present invention or a pharmaceutically acceptablesalt thereof, or a prodrug or metabolite thereof, can be applied tovarious apparatus in circumstances when the presence of such compoundswould be beneficial. Such apparatus can be any device or container, forexample, implantable devices in which a GSNOR inhibitor can be used tocoat a surgical mesh or cardiovascular stent prior to implantation in apatient. The GSNOR inhibitors of the present invention can also beapplied to various apparatus for in vitro assay purposes or forculturing cells.

The compounds of the present invention or a pharmaceutically acceptablesalt thereof, or a prodrug or metabolite thereof, can also be used as anagent for the development, isolation or purification of binding partnersto GSNOR inhibitor compounds, such as antibodies, natural ligands, andthe like. Those skilled in the art can readily determine related usesfor the compounds of the present invention.

EXAMPLES

The following examples are given to illustrate the present invention. Itshould be understood, however, that the invention is not to be limitedto the specific conditions or details described in these examples.Throughout the specification, any and all references to a publiclyavailable document, including a U.S. patent, are specificallyincorporated by reference.

Example 1 General and Specific Methods of Preparing Novel GSNOR PyrroleInhibitors

This example describes Schemes for preparing the GSNOR inhibitorsdepicted in Tables 1-4. Some schemes are specific to a particularcompound, while others are general schemes that include an exemplarymethod for preparing a representative compound. Following the schemesare Methods which describe the preparation of intermediates or startingmaterials that were used in select schemes.

Representative Procedure for Scheme 1 Synthesis of3-[1-(4-Carbamoyl-2-methyl-phenyl)-5-(4-methoxy-phenyl)-1H-pyrrol-2-yl]-propanoicacid

Step 1: Synthesis of (E)-3-Furan-2-yl-1-(4-methoxy-phenyl)-propenone. Asolution of 2-furaldehyde (5.85 g, 60.92 mmol) was added to a methanolsolution (120 mL) of 4-methoxy acetophenone (8.5 g, 56.6 mmol), followedby the addition of sodium methoxide (3.1 g, 56.6 mmol). The reactionmixture was stirred at room temperature for 16 h, followed by removal ofthe solvent in vacuo. The resultant mixture was diluted with water (130mL) and extracted with ethyl acetate (350 mL). The aqueous layer wasre-extracted with ethyl acetate (100 mL). The combined organic layerswere dried over anhydrous Na₂SO₄ and the solvent was removed in vacuo toobtain the product (E)-3-Furan-2-yl-1-(4-methoxy-phenyl)-propenone as anorange solid (12.6 g, 97%).

Step 2: Synthesis of 1-(4-Methoxy-phenyl)-decane-1,4,7-trione. Conc. HCl(59 mL) was added to a solution of(E)-3-Furan-2-yl-1-(4-methoxy-phenyl)-propenone (12.6 g, 55.2 mmol) inethanol (237 mL). The reaction mixture was heated under reflux for 16 h,concentrated, and diluted with dichloromethane (250 mL), and theresultant organic layer was washed with water (25 mL). After phaseseparation, the organic layer was dried over anhydrous Na₂SO₄ and thesolvent removed in vacuo to obtain the crude mixture, which was purifiedby silica gel flash chromatography to obtain1-(4-methoxy-phenyl)-decane-1,4,7-trione (6.89 g, 43%).

Step 3: Synthesis of3-[1-(4-Carbamoyl-2-methyl-phenyl)-5-(4-methoxy-phenyl)-1H-pyrrol-2-yl]propanoicacid ethyl ester. 4-amino-3-methylbenzamide (180 mg, 1.2 mmol) was addedto a solution 1-(4-methoxy-phenyl)-decane-1,4,7-trione (350 mg, 1.2mmol) in ethanol (6 mL), followed by the addition of p-toluenesulfonicacid monohydrate (23 mg, 0.12 mmol). The reaction mixture was heatedunder reflux for 16 h, and the solvent removed in vacuo to obtain acrude product which upon purification by silica gel flashchromatography, gives3-[1-(4-carbamoyl-2-methyl-phenyl)-5-(4-methoxy-phenyl)-1H-pyrrol-2-yl]propanoicacid ethyl ester (147 mg, 30%).

Step 4: Synthesis of3-[1-(4-Carbamoyl-2-methyl-phenyl)-5-(4-methoxy-phenyl)-1H-pyrrol-2-yl]-propanoicacid.3-[1-(4-carbamoyl-2-methyl-phenyl)-5-(4-methoxy-phenyl)-1H-pyrrol-2-yl]propanoicacid ethyl ester (86 mg, 0.216 mmol) was dissolved in ethanol (4 mL).Water (0.5 mL) was added to the ethanolic solution followed by theaddition of 1N NaOH (0.51 mL, 0.51 mmol). The reaction mixture wasstirred at room temperature for 1 h and then at 45° C. for an additionalhour. After removal of the solvent in vacuo, the residue was dilutedwith water (6 mL) and extracted with ethyl acetate (2×6 mL). The pH ofthe aqueous layer was adjusted to 2 with 1N HCl and then extracted withethyl acetate (6 mL). The combined organic layer was dried overanhydrous Na₂SO₄ and the solvent removed in vacuo to obtain3-[1-(4-Carbamoyl-2-methyl-phenyl)-5-(4-methoxy-phenyl)-1H-pyrrol-2-yl]-propanoicacid as the product (68 mg, 85%).

Representative Procedure for Scheme 1A, Alternate Conditions Synthesisof3-[1-(4-Carbamoyl-thiazol-2-yl)-5-(4-methoxy-phenyl)-1H-pyrrol-2-yl]-propionicacid

Step 3: Synthesis of3-[1-(4-Carbamoyl-thiazol-2-yl)-5-(4-methoxy-phenyl)-1H-pyrrol-2-yl]-propionicacid ethyl ester (1C, R1=4-carbamoyl-thiazol-2-yl, R2=4-methoxy-phenyl).To a solution of 7-(4-methoxy-phenyl)-4,7-dioxo-heptanoic acid ethylester (0.5 mmol), see scheme 1, in ethanol (2 mL) were added the amine(1.5 equivalents) and p-toluenesulfonic acid monohydrate (0.5 eq.). Thereaction was run using the Biotage Microwave Initiator for 1 to 3 hoursat 150° C. The solvent was removed in vacuo to obtain the crude mixturewhich was purified by prep silica gel plate to obtain the final product(70 mg, 38%).

Step 4: Synthesis of3-[1-(4-Carbamoyl-thiazol-2-yl)-5-(4-methoxy-phenyl)-1H-pyrrol-2-yl]-propionicacid (1D, R1=4-carbamoyl-thiazol-2-yl, R2=4-methoxy-phenyl). To3-[1-(4-Carbamoyl-thiazol-2-yl)-5-(4-methoxy-phenyl)-1H-pyrrol-2-yl]-propionicacid ethyl ester (0.15 mmol) in a 2:1 mixture of methanol/THF was added2M LiOH (0.30 mmol). The reaction mixture was stirred for 24 hours. Thesolvent was removed in vacuo. The residue was diluted with water (2 mL)and extracted with ethyl ether. The pH of the aqueous layer was adjustedto 2 with 1N HCl. The resulting suspension was filtered off; the solidwas washed with water and dried to give the final compound. Yield: 36mg, 69%.

Representative Procedure for Scheme 2 Synthesis of3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-carbamoylphenyl)-1H-pyrrol-2-yl)propanoicacid

Synthesis of 4-[(E)-3-(5-methoxy-furan-2-yl)-acryloyl]-benzamide. Sodiummethoxide (in portions) was added, over a time interval of about threeminutes, to 4-acetyl-benzamide (1.38 g, 8.5 mmol) and5-methoxy-furan-2-carbaldehyde (1.31 g, 10.6 mmol) in a 1:1 mixture ofmethanol and dimethylformamide (16 mL). The resulting solution wasplaced under N₂ and stirred overnight at 45° C. The reaction mixture wasthen evaporated to dryness under vacuum, followed by the addition ofwater and brine (100 mL) to the resulting residue. The aqueous solutionwas extracted with ethyl acetate (125 mL×3) and the combined organiclayers were washed with brine (100 mL) and dried over MgSO₄. The crudereaction mixture of 4-[(E)-3-(5-methoxy-furan-2-yl)-acryloyl]-benzamideand unreacted 4-acetyl acetamide is used without purification.

Synthesis of 4-[3-(5-methoxy-furan-2-yl-propionyl]-benzamide. 10% Pd/C(60 mg) was added to crude4-[(E)-3-(5-methoxy-furan-2-yl)-acryloyl]-benzamide (180 mg) in THF (4mL). The mixture was subjected to hydrogenation at 45 psi for 4 hours.After removal of the catalyst by filtration through celite, the mixturewas concentrated and carried forward without any purification.

Synthesis of 7-(4-carbamoyl-phenyl)-4,7-dioxo-heptanoic acid. Crude4-[3-(5-methoxy-furan-2-yl-propionyl]-benzamide (175 mg) was dissolvedin 10% aqueous methanol (3 mL) to which was added 0.2 N HCl (0.2 mL) soas to obtain a solution having a final pH=3. The resulting solution wasstirred for 30 minutes, evaporated to dryness and subjected tochromatographic purification using dichloromethane as the solvent (53mg) of material with 67% purity.

Synthesis of3-[1-carbamoyl-2-methyl-phenyl)-5-(4-carbamoyl-phenyl)-1H-pyrrole-2-yl]-propanoicacid methyl ester. 4-amino-3-methyl benzamide (20 mg, 0.13 mmol) wasadded to 7-(4-carbamoyl-phenyl)-4,7-dioxo-heptanoic acid ethyl estermixture (˜0.11 mmol) in EtOH, followed by the addition ofp-toluenesulfonic acid (2 mg, 0.01 mmol). The resultant mixture washeated at 80° C. for 12 hours. The residue of the crude reaction mixturewas dissolved in dichloromethane and then purified by silica-gelchromatography using 5% methanol in chloroform as the solvent system (5mg; product:3-[1-carbamoyl-2-methyl-phenyl)-5-(4-carbamoyl-phenyl)-1H-pyrrole-2-yl]-propanoicacid methyl ester).

Synthesis of3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-carbamoylphenyl)-1H-pyrrol-2-yl)propanoicacid.3-[1-carbamoyl-2-methyl-phenyl)-5-(4-carbamoyl-phenyl)-1H-pyrrole-2-yl]-acidmethyl ester was hydrolyzed using the procedure described above in thefinal step of scheme 1 (product: 4.8 mg).

Representative Procedure for Scheme 3 Synthesis of3-(5-(4-(1H-pyrazol-4-yl)phenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoicacid

Synthesis of3-[1-(4-Carbamoyl-2-methyl-phenyl)-5-(4-iodo-phenyl)-1H-pyrrol-2-yl]-propanoicacid ethyl ester. The titled compound was prepared according to thefirst 3 steps of Scheme 1, (where R₂=4-iodo-phenyl, andR₁=4-carbamoyl-2-methylphenyl).

Synthesis of ethyl3-(5-(4-(1H-pyrazol-4-yl)phenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoate.A mixture of3-[1-(4-Carbamoyl-2-methyl-phenyl)-5-(4-iodo-phenyl)-1H-pyrrol-2-yl]-propanoicacid ethyl ester (127 mg, 0.252 mmol), 1H-pyrazole boronic acid pinacolester (147 mg, 0.75 mmol), potassium acetate (222 mg, 2.3 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (60.0 mg,0.074 mmol) in anhydrous DMF (4 mL) was degassed with nitrogen and thenheated at 100° C. for 16 h. The mixture was then diluted with ethylacetate (50 mL) and washed with water (30 mL). After drying the organiclayer over anhydrous Na₂SO₄, the solvent was removed to obtain a crudeproduct which is purified by silica gel flash chromatography (33 mg,28%).

Synthesis of3-(5-(4-(1H-pyrazol-4-yl)phenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoicacid. To the product from step 1 (33 mg, 0.074 mmol) in ethanol (0.5 mL)was added 1N NaOH (88 μL, 0.089 mmol). The reaction mixture was stirredat room temperature for 16 h, followed by removal of the solvent invacuo. The resultant residue was diluted with water (4 mL) and extractedwith ethyl acetate (5 mL). The pH of the aqueous layer was then adjustedto 4 pH units using 1N HCl. This results in the precipitation of a solidwhich was filtered and dried to give the product3-(5-(4-(1H-pyrazol-4-yl)phenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoicacid (12 mg, 38%).

Representative Procedure for Scheme 4 Synthesis of3-[5-(4-aminophenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl]-propanoicacid

Synthesis of3-[1-(4-carbamoyl-2-methyl-phenyl)-5-(4-nitro-phenyl)-1H-pyrrole-2-yl]-propanoicacid ethyl ester. The titled compound was prepared according to thefirst 3 steps of Scheme 1, R₂=4-nitro-phenyl, andR₁=4-carbamoyl-2-methylphenyl).

Synthesis of3-[5-(4-aminophenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl]-propanoicacid ethyl ester.3-[1-(4-carbamoyl-2-methyl-phenyl)-5-(nitro-phenyl)-1H-pyrrole-2-yl]-propanoicacid ethyl ester (83 mg, 0.2 mmol) was dissolved in 2 mL methanol underan inert atmosphere of nitrogen. To this solution was added ammoniumformate (117 mg, 1.8 mmol) and 10% Pd/C (10 mg). After 24 hrs, thereaction mixture was filtered using celite, rinsed with MeOH andconcentrated in vacuo. The residue was diluted with acetone, filteredand the filtrate concentrated in vacuo to give the crude product, whichwas purified using preparative TLC (solvent: 5% IPA/CH₂Cl₂). The bandcorresponding to3-[5-(4-aminophenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl]-propanoicacid ethyl ester (R_(f)=0.6) was isolated and dried under high vacuum(36 mg, 77%, light orange hydroscopic powder).

Synthesis of3-[5-(4-aminophenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl]-propanoicacid.3-[5-(4-aminophenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl]propanoicacid ethyl ester (36 mg, 0.09 mmol) was dissolved in 1 mL methanol. 1 NNaOH (0.18 mL, 0.18 mmol.) was added. After 18 hrs, the reaction wasconcentrated in vacuo and diluted with water. The pH was adjusted to 1with 1 M HCl and extracted with EtOAc (3×4 mL). The combined organiclayers were dried over Na₂SO₄, filtered and concentrated in vacuo. Theresidue was triturated with hexanes and dried under high vacuum to yield3-[5-(4-aminophenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl]-propanoicacid (16 mg, 50%, light orange powder).

Representative Procedure for Scheme 5 Synthesis of3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoicacid

Step 1: Synthesis of 1-(4-bromophenyl)-3-(furan-2-yl)prop-2-en-1-one(5A). To a solution of 4-bromophenylethanone (112.6 g, 570 mmol) andfuran-2-carbaldehyde (58.5 g, 610 mmol) in methanol (1.5 L) was addedCH₃ONa (31 g, 570 mmol) over 10 min and the reaction solution wasstirred at room temperature overnight. The reaction mixture wasneutralized with conc. HCl to pH=7, and the solvent was removed underreduced pressure. To the resultant residue was added EA and water. Theaqueous layer was extracted with EA for 3 times. The combined layerswere washed with brine, dried over MgSO₄, concentrated and purified bysilica gel column chromatography (PE:EA=10:1) to afford1-(4-bromophenyl)-3-(furan-2-yl)prop-2-en-1-one (5A) as a yellow solid(90.2 g, 65%).

Step 2: Synthesis of ethyl 7-(4-bromophenyl)-4,7-dioxoheptanoate (5B).To a solution of compound1-(4-bromophenyl)-3-(furan-2-yl)prop-2-en-1-one (5A) (20.0 g, 72.2 mmol)in ethanol (160 mL) was added HBr (48% in water, 40 mL). The resultantmixture was stirred under reflux for 8 h, and then the reaction solutionwas concentrated in vacuo. To the residue was added sat. NaHCO₃ to PH=7and extracted with EA. The combined organic layers were washed withbrine, dried over MgSO₄, concentrated and purified by silica gel columnchromatography (PE:EA=5:1) to afford ethyl7-(4-bromophenyl)-4,7-dioxoheptanoate (5B) as a yellow solid (7.0 g,28%).

Step 3: Synthesis of Ethyl3-(5-(4-bromophenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoate.To a solution of ethyl 7-(4-bromophenyl)-4,7-dioxoheptanoate (5B) (3.41g, 10 mmol) and 4-amino-3-methylbenzamide (1.65 g, 11 mmol) in 50 mL ofethanol was added TsOH.H₂O (570 mg, 3 mmol). The reaction solution wasstirred under reflux overnight and then concentrated in vacuo. Theresultant residue was neutralized with sat. NaHCO₃ and extracted withEthyl Acetate. The organic layers were washed with brine, concentratedand purified by silica gel column chromatography (DCM:PE=1:1) to affordethyl 7-(4-bromophenyl)-4,7-dioxoheptanoate as a pale solid (2.80 g,61%).

Step 4: Synthesis of ethyl3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoate.To a mixture of ethyl 7-(4-bromophenyl)-4,7-dioxoheptanoate (4.54 g, 10mmol) and imidazole (2.04 g, 30 mmol) in DMSO (50 mL) was addedL-proline (0.345 g, 3 mmol), CuI (1.14 g, 6 mmol) and K₂CO₃ (2.76 g, 20mmol). The resultant mixture was stirred under N₂ at 100° C. overnight,cooled to room temperature, filtered, and concentrated in vacuum. Theresidue was dissolved in ethyl acetate and saturated aqueous NaHCO₃ wasadded till pH=8.5. The mixture was filtered and the resultant aqueouslayer was extracted with EA (5 times). The combined organic layers werewashed with brine, dried over MgSO₄, concentrated and purified by silicagel column chromatography (DCM:MeOH=30:1-20:1) to afford3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoateas a pale solid (1.6 g, 36%).

Step 5: Synthesis of3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoicacid. To a solution of compound3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoate(22.0 g, 48.3 mmol) in THF/H₂O (v/v=1/1, 220 mL) was added LiOH.H₂O(4.15 g, 96.6 mmol). The reaction solution was stirred at roomtemperature for 5 h. The THF was removed under reduced pressure and theaqueous solution was acidified with 10% HCl to pH=5. The solid wasfiltered and recrystallized from THF and water [1:1(v/v)] to afford3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoicacid as a yellow solid (11.35 g, 55%).

Representative Procedure for Scheme 6 Synthesis of3-(5-(benzo[d][1,3]dioxol-5-yl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoicacid

Step 1: Synthesis of 3-methyl-4-(1H-pyrrol-1-yl)benzamide (6A). The2,5-dimethoxy-tetrahydrofuran (106 g, 80 mmol) was added to the solutionof 4-amino-3-methylbenzamide (100 g, 66.7 mmol) in AcOH (300 mL). Themixture was stirred at 80° C. for about 1.5 h and then cooled to roomtemperature. The solution of Na₂CO₃ was added dropwise at 0° C. andextracted with ethyl acetate for three times. The combined organiclayers were washed with brine, dried over Na₂SO₄, concentrated andwashed with petroleum ether. The resultant solid was filtrated and driedto afford 3-methyl-4-(1H-pyrrol-1-yl)benzamide as a pale solid (89.7 g,yield 67%).

Step 2: Synthesis of 4-(2-formyl-1H-pyrrol-1-yl)-3-methylbenzonitrile(6B). POCl₃ (65 g, 427 mmol) was added to DMF (34 mL) at 0° C. for 30min. After addition, the mixture was stirred at room temperature for 1.5h, and then cooled to 0° C. A solution of3-methyl-4-(1H-pyrrol-1-yl)benzamide (6A) (42.7 g, 213.5 mmol) in DMF(150 mL) was added at 0° C. and the resultant mixture was stirred atroom temperature for 20 min, and then heated to 80° C. for 1 h. Thesolution was cooled to room temperature and then sat. Na₂CO₃ was addedat 0° C. until pH=8. The mixture was extracted with ethyl acetate threetimes. The combined organic layers were washed with sat. NaHCO₃ andbrine, dried over Na₂SO₄, concentrated and purified by silica gel columnchromatography (PE:EA=10:1) to afford4-(2-formyl-1H-pyrrol-1-yl)-3-methylbenzonitrile as a yellow solid (30.5g, yield 68%).

Step 3: Synthesis of ethyl3-(1-(4-cyano-2-methylphenyl)-1H-pyrrol-2-yl)acrylate (6C)

Method A: The mixture of4-(2-formyl-1H-pyrrol-1-yl)-3-methylbenzonitrile (15 g, 71.4 mmol) and(carbethoxymethylene)-triphenylphosphorane (27.5 g, 78.6 mmol) intoluene was heated to 100° C. overnight. Then it was cooled to roomtemperature, concentrated and purified by silica gel columnchromatography (PE:EA=5:1) to afford ethyl3-(1-(4-cyano-2-methylphenyl)-1H-pyrrol-2-yl)acrylate as a yellow oil(19.8 g, 98%).

Method B: To a mixture of4-(2-formyl-1H-pyrrol-1-yl)-3-methylbenzonitrile (24.5 g, 116.7 mmol),DMAP (2.9 g, 23.3 mmol) and potassium monoethyl malonate (99.2 g, 583.3mmol) in DMF (600 mL) was added AcOH (35.0 g, 583.3 mmol) and piperidine(29.8 g, 350 mmol). The resultant mixture was heated to 80° C. andstirred for 48 h. The reaction mixture was poured into cooled water andextracted with ethyl acetate (800 mL×3). The combined organic layerswere washed with sat. NaHCO₃ and brine, dried over Na₂SO₄, concentratedand purified by silica gel column chromatography (PE:EA=5:1) to affordethyl 3-(1-(4-cyano-2-methylphenyl)-1H-pyrrol-2-yl)acrylate as a yellowoil (21.8 g, 67%).

Step 4: Synthesis of ethyl3-(1-(4-cyano-2-methylphenyl)-1H-pyrrol-2-yl)propanoate (6D). To asolution of ethyl 3-(1-(4-cyano-2-methylphenyl)-1H-pyrrol-2-yl)acrylate(6C) (8.0 g, 28.6 mmol) in ethanol was added 10% Pd/C (0.8 g). Themixture was stirred under 1 atm of H₂ for 30 min at room temperature andfiltrated. The resultant filtrate was concentrated to dryness affordingthe crude product of ethyl3-(1-(4-cyano-2-methylphenyl)-1H-pyrrol-2-yl)propanoate (7.5 g), whichwas used for the next step without further purification: LC-MS m/z 283.0[M+H]⁺, purity 68%.

Step 5: Synthesis of ethyl3-(5-bromo-1-(4-cyano-2-methylphenyl)-1H-pyrrol-2-yl)propanoate (6E).NBS (4.76 g, 1 equiv) was added portionwise to a solution of ethyl3-(1-(4-cyano-2-methylphenyl)-1H-pyrrol-2-yl)propanoate in DMF at 0° C.during 45 min. After addition, the mixture was stirred at roomtemperature for 30 min, then poured into water, and extracted with ethylacetate for three times. The combined organic layers were washed withbrine, dried over Na₂SO₄, concentrated and purified by silica gel columnchromatography (PE:EA=15:1) to afford ethyl3-(5-bromo-1-(4-cyano-2-methylphenyl)-1H-pyrrol-2-yl)propanoate as awhite solid.

Step 6: Synthesis of ethyl3-(5-(benzo[d][1,3]dioxol-5-yl)-1-(4-cyano-2-methylphenyl)-1H-pyrrol-2-yl)propanoate.To a suspension of ethyl3-(5-bromo-1-(4-cyano-2-methylphenyl)-1H-pyrrol-2-yl)propanoate (400 mg,0.665 mmol), 3,4-methylenedioxylphenylboric acid (143 mg, 0.864 mmol),sodium bicarbonate (560 mg, 5.32 mmol) in solvent (4 mL) was addedPd(PPh₃)₄ (60 mg, 0.199 mmol). The reaction was degassed and heated toreflux for 5 h. TLC showed that the reaction was completed. Water (4 mL)was added and the mixture was extracted with ethyl acetate (5 mL×3). Thecombined organic layers were dried with magnesium sulfate, filtered andevaporated to obtain a brown oil, which was purified by silica gelcolumn chromatography to afford ethyl3-(5-(benzo[d][1,3]dioxol-5-yl)-1-(4-cyano-2-methylphenyl)-1H-pyrrol-2-yl)propanoateas a colorless oil (308 mg, 69%).

Step 7 and Step 8: Synthesis of3-(5-(benzo[d][1,3]dioxol-5-yl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoicacid. To a mixture of ethyl3-(5-(benzo[d][1,3]dioxol-5-yl)-1-(4-cyano-2-methylphenyl)-1H-pyrrol-2-yl)propanoate(100 mg, 0.249 mmol) and potassium carbonate (52 mg, 0.373 mmol) in DMSO(1 mL) was added 30% aqueous H₂O₂ (28.2 mg, 0.249 mmol). The resultantmixture was stirred at room temperature for 2 h. TLC showed the reactionwas completed. Water (7 mL) was added and white solid precipitated. Thesuspension was centrifuged and the aqueous phase was discarded. Theresultant solid was dried in vacuum to afford the amide intermediate asa white solid (85 mg, yield 81%). To the mixture of this intermediate inH₂O (0.6 mL) and THF (0.6 mL) was added LiOH H₂O (10 mg, 0.238 mmol).The reaction mixture was stirred at room temperature overnight. THF wasevaporated in vacuum. The residue was acidified to pH=4 with 5%hydrochloric acid, centrifuged and dried to afford3-(5-(benzo[d][1,3]dioxol-5-yl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoicacid as a white solid (46 mg, overall yield 47%).

Representative Procedure for Scheme 7 Synthesis of3-(5-(4-(2-amino-2-oxoethoxy)phenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoicacid

Synthesis of3-(5-(4-(2-amino-2-oxoethoxy)phenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoicacid (7B).3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-hydroxyphenyl)-1H-pyrrol-2-yl)propanoicacid (7A, R1=4-carbamoyl-2-methylphenyl) was prepared according to themethodology shown in Scheme 1, R2=4-hydroxyphenyl,R1=4-carbamoyl-2-methylphenyl. A N,N-dimethylformamide solution of3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-hydroxyphenyl)-1H-pyrrol-2-yl)propanoicacid (36 mg, 0.1 mmol, 1 ml), potassium carbonate (27 mg, 0.2 mmol) and2-bromoacetamide (18 mg, 0.12 mmol) was stirred for 18 hrs at ambienttemperature, after which time the reaction was diluted with water andthe pH adjusted to 2 with 1 M HCl. The aqueous layer was extracted withEtOAc (3×3 mL), dried over N₂SO₄, filtered and concentrated in vacuo.The residue thus obtained was triturated with hexanes and dried underhigh vacuum to yield the title compound as a light yellow powder (13mg).

Representative Procedure for Scheme 8 Synthesis of3-[1-(4-carbamoyl-2-methylphenyl)-5-[4-(2-oxo-imidazolidin-1-yl)-phenyl]-1H-pyrrol-2-yl]-propionicacid

Synthesis of3-[1-(4-carbamoyl-2-methylphenyl)-5-[4-(2-oxo-imidazolidin-1-yl)-phenyl]-1H-pyrrol-2-yl]-propionicacid ethyl ester. In a 2.5 mL microwave reaction vial,3-[1-(4-carbamoyl-2-methyl-phenyl)-5-((4-iodo-phenyl)-1H-2-yl]-propionicacid ethyl ester 8A (which was prepared according to the first 3 stepsof Scheme 1, R₂=4-iodo-phenyl, and R₁=4-carbamoyl-2-methylphenyl) (51mg, 0.1 mmol), 2-imidazolidone (44 mg, 0.5 mmol), CuI (5 mg, 0.02 mmol),N,N′ dimethylethylenediamine (DMEDA) (0.01 mL, 0.04 mmol), and potassiumphosphate tribasic (44 mg, 0.2 mmol) were dissolved in 0.5 mL anhydrousN,N-dimethylformamide. The vial was purged with nitrogen, sealed andplaced in microwave reactor at 120° C. for 20 min. TLC (10% IPA/CH₂Cl₂)showed reaction 50% complete. CuI (5 mg) and 2-imidazolidone (40 mg)were added; the reaction was repurged with nitrogen, sealed and placedin microwave reactor at 130° C. for 20 min. Reaction was filtered overcelite, rinsed with EtOAc and concentrated in vacuo. The crude productwas purified by preparative plate TLC (5% MeOH/CH₂Cl₂). Desired band(rf=0.28) was isolated and dried under high vacuum to yield intermediate3-[1-(4-carbamoyl-2-methylphenyl)-5-[4-(2-oxo-imidazolidin-1-yl)-phenyl]-1H-pyrrol-2-yl]-propionicacid ethyl ester (43 mg, 93%, dark yellow solid).

3-[1-(4-carbamoyl-2-methylphenyl)-5-[4-(2-oxo-imidazolidin-1-yl)-phenyl]-1H-pyrrol-2-yl]-propionicacid.3-[1-(4-carbamoyl-2-methylphenyl)-5-[4-(2-oxo-imidazolidin-1-yl)-phenyl]-1H-pyrrol-2-yl]-propionicacid ethyl ester (43 mg, 0.10 mmol) was hydrolyzed according toprocedure described above in the final step of scheme 4 (52%, lightorange hygroscopic solid).

Representative Procedure for Scheme 9a Synthesis of3-(5-(4-(1H-pyrazol-1-yl)phenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoicacid

Synthesis of3-[1-(4-carbamoyl-2-methyl-phenyl)-5-(4-pyrazole-1-yl-phenyl)-1H-pyrrol-2-yl]-propionicacid ethyl ester (9a-B, Ar=1H-pyrazol-1-yl).N,N-dimethyl-cyclohexane-1,2-diamine (11 mg, 0.08 mmol) was dissolved inDMSO and degassed by bubbling argon through the solution for 2 minutes.The resulting solution was then added to a mixture of3-[1-(4-carbamoyl-2-methyl-phenyl)-5-(4-iodo-phenyl)-1H-pyrrole-2-yl]-propionicacid ethyl ester 8A (which was prepared according to the first 3 stepsof Scheme 1, R₂=4-iodo-phenyl, and R₁=4-carbamoyl-2-methylphenyl) (150mg, 0.29 mmol), pyrazole (500 mg, 7.5 mmol), copper iodide (11 mg, 0.06mmol), and potassium carbonate (86 mg (0.61 mmole) and the resultingreaction mixture again degassed for 2 minutes by bubbling argon gasthrough the solution. The reaction mixture was then submitted tomicrowave irradiation for 30 minutes at 120° C. The reaction mixture wasthen added to water (10 mL), extracted into ethyl acetate (3×10 mL). Theethyl acetate extracts were combined, washed with water (5 mL) and thenbrine (5 mL). The organic layer was then dried over MgSO₄.Chromatography (5 g silica sep-pak cartridge) with dichloromethane then1% methanol in dichloromethane yielded pure intermediate3-[1[(4-carbamoyl-2-methyl-phenyl)-5-(4-pyrazole-1-yl)-1Hpyrrol-2-yl]-propionicacid ethyl ester (26 mg, 20%).

Synthesis of3-(5-(4-(1H-pyrazol-1-yl)phenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoicacid (9a-C, Ar=1H-pyrazol-1-yl).3-[1-(4-carbamoyl-2-methyl-phenyl)-5-(4-pyrazole-1-yl-phenyl)-1H-pyrrol-2-yl]-propionicacid ethyl ester (24 mg, 0.06 mmol) was hydrolyzed using the proceduredescribed above in the final step of scheme 4 to give the titlecompound,3-[1[(4-carbamoyl-2-methyl-phenyl)-5-(4-pyrazole-1-yl)-1Hpyrrol-2-yl]-propionicacid (18 mg, 75%).

A Second Representative Procedure for Scheme 9a Synthesis of3-{1-(4-carbamoyl-2-methyl-phenyl)-5-[4-(2-methyl-imidazole-1-yl)phenyl-1-yl]-1H-pyrrole-2-yl}-propionicacid

Synthesis of3-{1-(4-carbamoyl-2-methyl-phenyl)-5-[4-(2-methyl-imidazole-1-yl)phenyl-1-yl]-1H-pyrrole-2-yl}-propionicacid ethyl ester. Step one run as above on 120 mg 8A (0.24 mmol), exceptat 150° C. under microwave irradiation for 2×45 minutes to provide 50 mgof titled compound (45%).

Synthesis of3-{1-(4-carbamoyl-2-methyl-phenyl)-5-[4-(2-methyl-imidazole-1-yl)phenyl-1-yl]-1H-pyrrole-2-yl}-propionicacid. Step two was run on3-{1-(4-carbamoyl-2-methyl-phenyl)-5-[4-(2-methyl-imidazole-1-yl)phenyl-1-yl]-1H-pyrrole-2-yl}-propionicacid ethyl ester (85 mg, 0.2 mmol) as above (following final step ofscheme 4) with isolation as follows: The reaction mixture wasconcentrated to half by N₂ stream and washed with EtOAc. One equivalentof 1N HCl was added to the reaction mixture, which was then evaporatedto dryness and taken up in 0.5 mL water. The mixture was then purifiedon a reverse phase C18 column to isolate product from salts. Yield:3-{1-(4-carbamoyl-2-methyl-phenyl)-5-[4-(2-methyl-imidazole-1-yl)phenyl-1-yl]-1H-pyrrole-2-yl}-propionicacid, 36 mg, 42%.

Representative Procedure for Scheme 9b Synthesis of3-[1-(4-carbamoyl-2-methyl-phenyl)-5-(5-imidazole-1-yl-thiophene-2-yl)-1H-pyrrole-2-yl]-propionicacid

Synthesis of3-[1-(4-carbamoyl-2-methyl-phenyl)-5-(5-imidazole-1-yl-thiophene-2-yl)-1H-pyrrole-2-yl]-propionicacid ethyl ester. Prepared using same protocol as Step 1 of Scheme 9aexcept starting with ethyl3-(5-(5-bromothiophen-2-yl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoate(which was prepared according to the first 3 steps of Scheme 1,R₂=5-bromothiophen-2-yl, and R₁=4-carbamoyl-2-methylphenyl).

Synthesis of3-[1-(4-carbamoyl-2-methyl-phenyl)-5-(5-imidazole-1-yl-thiophene-2-yl)-1H-pyrrole-2-yl]-propionicacid.3-[1-(4-carbamoyl-2-methyl-phenyl)-5-(5-imidazole-1-yl-thiophene-2-yl)-1H-pyrrole-2-yl]-propionicacid ethyl ester was hydrolyzed according to the procedure described inthe final step of scheme 4 to give the title compound3-[1-(4-carbamoyl-2-methyl-phenyl)-5-(5-imidazole-1-yl-thiophene-2-yl)-1H-pyrrole-2-yl]-propionicacid.

Representative Procedure for Scheme 10 Synthesis of3-[1-(4-carbamoyl-2-methyl-phenyl)-5-(4-morpholin-4-yl-phenyl-1H-pyrrole-2-yl]-propionicacid

Synthesis of3-[1-(4-carbamoyl-2-methyl-phenyl)-5-(4-morpholin-4-yl-phenyl-1H-pyrrole-2-yl]-propionicacid ethyl ester. L-proline (14 mg, 0.08 mmol) was dissolved in DMSO anddegassed by bubbling argon through the solution for 2 minutes. Theresulting solution was then added to a mixture of3-[1-(4-carbamoyl-2-methyl-phenyl)-5-(4-iodo-phenyl)-1H-pyrrole-2-yl]-propionicacid ethyl ester (8A) (150 mg, 0.29 mmol), morpholine (0.60 mL, 7.5mmol), copper iodide (11 mg, 0.06 mmol), and potassium carbonate (86 mg(0.61 mmole) and the resulting reaction mixture again degas sed for 2minutes by bubbling argon gas through the solution. The reaction mixturewas then submitted to microwave irradiation for 30 minutes at 120° C.The reaction mixture was then added to ethyl acetate (30 mL), washedwith water (2×8 mL), saturated ammonium chloride (5×4 mL), water (5 mL)and brine (5 mL). It was then dried over MgSO₄. Chromatography (5 gsep-pak cartridge) 2% methanol in dichloromethane yielded3-[1-(4-carbamoyl-2-methyl-phenyl)-5-(4-morpholin-4-yl-phenyl-1H-pyrrole-2-yl]-propionicacid ethyl ester (80 mg, 53%).

Synthesis of3-[1-(4-carbamoyl-2-methyl-phenyl)-5-(4-morpholin-4-yl-phenyl-1H-pyrrole-2-yl]-propionicacid.3-[1-(4-carbamoyl-2-methyl-phenyl)-5-(4-morphylin-1-yl-phenyl)-1H-pyrrol-2-yl]-propionicacid ethyl ester (50 mg, 0.11 mmol) was hydrolyzed using the proceduredescribed above in the final step of Scheme 4 to give the titlecompound,3-[1-(4-carbamoyl-2-methyl-phenyl)-5-(4-morpholin-4-yl-phenyl-1H-pyrrole-2-yl]-propionicacid (37 mg, 74%).

Synthesis of3-[1-(4-carbamoyl-2-methylphenyl)-5-(4-[1,2,4]triazol-4-yl-phenyl)-1H-pyrrol-2-yl]-propionicacid ethyl ester (11B). Under a nitrogen atmosphere,3-[5-(4-aminophenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl]-propionicacid ethyl ester (11A, synthesis described in Scheme 4 whereR1=4-carbamoyl-2-methylphenyl) (102 mg, 0.26 mmol) was dissolved in 4 mLpyridine. 1,2-diformylhydrazine (69 mg, 0.78 mmol) was added.Chlorotrimethylsilane (0.5 mL, 3.9 mmol) was added dropwise.Triethylamine (0.25 mL, 1.82 mmol) was added dropwise. The reaction washeated to 100° C. for 24 hrs. After cooling, the reaction was dilutedwith water and extracted with ethyl acetate. The combined organic layerswere washed with brine, dried over Na₂SO₄, filtered and concentrated invacuo. The crude material was purified by preparative tlc plate (1500microns, 10% IPA/CH₂Cl₂). The desired band (rf=0.3) was isolated anddried under high vacuum to yield3-[1-(4-carbamoyl-2-methylphenyl)-5-(4-[1,2,4]triazol-4-yl-phenyl)-1H-pyrrol-2-yl]-propionicacid ethyl ester (11B) (95 mg, 82%, light tan powder).

Synthesis of3-[1-(4-carbamoyl-2-methylphenyl)-5-(4-[1,2,4]triazol-4-yl-phenyl)-1H-pyrrol-2-yl]-propionicacid (11C).3-[1-(4-carbamoyl-2-methylphenyl)-5-(4-[1,2,4]triazol-4-yl-phenyl)-1H-pyrrol-2-yl]-propionicacid ethyl ester (11B) (95 mg, 0.21 mmol) was hydrolyzed according tothe procedure described above in the final step of Scheme 4 to give thetitle compound,3-[1-(4-carbamoyl-2-methylphenyl)-5-(4-[1,2,4]triazol-4-yl-phenyl)-1H-pyrrol-2-yl]-propionicacid (11C) (43 mg, 48%, light yellow powder).

Synthesis of3-[1-(4-carbamoyl-2-methylphenyl)-5-(4-tetrazol-1-yl-phenyl)-1H-pyrrol-2-yl]-propionicacid ethyl ester (12B). Under a nitrogen atmosphere,3-[5-(4-aminophenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl]-propionicacid ethyl ester (11A, synthesis described in Scheme 4 whereR1=4-carbamoyl-2-methylphenyl) (102 mg, 0.26 mmol) was dissolved in 2 mLglacial acetic acid. Trimethylorthoformate (0.1 mL, 0.78 mmol) wasadded. The mixture was stirred for 20 min. at room temperature. Sodiumazide (25 mg, 0.39 mmol) was added and the reaction was heated to 80° C.for 2 hrs. After cooling, the reaction was diluted with water (3 mL) andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over Na₂SO₄, filtered and concentrated in vacuo. Thecrude material was purified by preparative TLC plate (1500 microns, 10%IPA/CH₂Cl₂). The desired band (rf=0.5) was isolated and dried under highvacuum to yield3-[1-(4-carbamoyl-2-methylphenyl)-5-(4-tetrazol-1-yl-phenyl)-1H-pyrrol-2-yl]-propionicacid ethyl ester (12B) (71 mg, 60%, light orange powder).

Synthesis of3-[1-(4-carbamoyl-2-methylphenyl)-5-(4-tetrazol-1-yl-phenyl)-1H-pyrrol-2-yl]-propionicacid (12C).3-[1-(4-carbamoyl-2-methylphenyl)-5-(4-tetrazol-1-yl-phenyl)-1H-pyrrol-2-yl]-propionicacid ethyl ester (12B) (71 mg, 0.16 mmol) was hydrolyzed according tothe procedure described above in the final step of scheme 4 to give thetitle compound,3-[1-(4-carbamoyl-2-methylphenyl)-5-(4-tetrazol-1-yl-phenyl)-1H-pyrrol-2-yl]-propionicacid (12C) (50 mg, 75%, off-white powder).

Synthesis of3-[1-(4-carbamoyl-2-methylphenyl)-5-(4-phenoxycarbonylaminophenyl)-1H-pyrrol-2-yl]-propionicacid ethyl ester (13B). Under a nitrogen atmosphere,3-[5-(4-aminophenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl]-propionicacid ethyl ester (11A, synthesis described in Scheme 4 whereR1=4-carbamoyl-2-methylphenyl) (106 mg, 0.26 mmol) was dissolved in 1 mLmethylene chloride. The mixture was cooled in an ice bath. Hünig's base(0.12 mL, 0.65 mmol) was added. Phenylcarbamate (0.05 mL, 0.39 mmol) wasadded dropwise. The reaction was stirred at 0° C. for 30 min, and thenallowed to warm to room temperature. After 24 hrs, 3 mL THF/3 mL sodiumbicarbonate was added and stirred for 40 min. Then ethyl acetate (3 mL)was added and the layers separated. The aqueous layer was furtherextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over Na₂SO₄, filtered and concentrated in vacuo. Thecrude material was purified by preparative TLC plate (1500 microns, 5%MeOH/CH₂Cl₂). The desired band (rf=0.51) was isolated and dried underhigh vacuum to yield3-[1-(4-carbamoyl-2-methylphenyl)-5-(4-phenoxycarbonylaminophenyl)-1H-pyrrol-2-yl]-propionicacid ethyl ester (13B) (66 mg, 48%, hygroscopic tan powder).

Synthesis of3-[1-(4-carbamoyl-2-methylphenyl)-5-(4-ureidophenyl)-1H-pyrrol-2-yl]-propionicacid ethyl ester (13C). Under a nitrogen atmosphere, ammonium hydroxide(2 mL) was slowly added to3-[1-(4-carbamoyl-2-methylphenyl)-5-(4-phenoxycarbonylaminophenyl)-1H-pyrrol-2-yl]-propionicacid ethyl ester (13B) (66 mg, 0.13 mmol). Dimethylsulfoxide (1 mL) wasslowly added. The reaction was then heated to 85° C. for 24 hrs. Aftercooling, the reaction was diluted with water and extracted with ethylacetate. The combined organic layers were dried over Na₂SO₄, filteredand concentrated in vacuo. The crude material was purified bypreparative TLC plate (1500 microns, 10% IPA/CH₂Cl₂). The desired band(rf=0.2) was isolated and dried under high vacuum to yield3-[1-(4-carbamoyl-2-methylphenyl)-5-(4-ureidophenyl)-1H-pyrrol-2-yl]-propionicacid ethyl ester (13C) (20 mg, 35%, light yellow powder).

Synthesis of3-[1-(4-carbamoyl-2-methylphenyl)-5-(4-ureidophenyl)-1H-pyrrol-2-yl]-propionicacid (13D).3-[1-(4-carbamoyl-2-methylphenyl)-5-(4-ureidophenyl)-1H-pyrrol-2-yl]-propionicacid ethyl ester (13C) (20 mg, 0.05 mmol) was hydrolyzed according tothe procedure described above in the final step of scheme 4 to give thetitle compound,3-[1-(4-carbamoyl-2-methylphenyl)-5-(4-ureidophenyl)-1H-pyrrol-2-yl]-propionicacid (13D) (9.0 mg, 48%, light yellow powder).

Synthesis of3-[1-(4-carbamoyl-2-methylphenyl)-5-(4-methanesulfonylaminophenyl)-1H-pyrrol-2-yl]-propionicacid

Step 1: Under nitrogen atmosphere,3-[1-(4-carbamoyl-2-methyl-phenyl)-5-(amino-phenyl)-1H-pyrrole-2-yl]-propionicacid ethyl ester (11A, synthesis described in Scheme 4 whereR1=4-carbamoyl-2-methylphenyl) (51 mg, 0.13 mmol) was dissolved in 1 mLanhydrous THF. Triethylamine (0.04 mL, 0.26 mmol) and then methanesulfonylchloride (0.01 mL, 0.13 mmol) were added. After 18 hrs, 0.01 mLmethane sulfonylchloride was added to push the reaction to completion.After another 18 hrs, the reaction was diluted with water and extractedwith EtOAc (3×5 mL). The combined organic layers were dried over Na₂SO₄,filtered and concentrated in vacuo. The crude material was purified bypreparative TLC plate (5% MeOH/CH₂Cl₂). 14B, ethyl3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(methylsulfonamido)phenyl)-1H-pyrrol-2-yl)propanoatewas isolated, rf=0.17 (28 mg, 50%).

Step 2: Product 14B (28 mg, 0.052 mmol) was hydrolyzed according to theprocedure described above in the final step of scheme 4 to give thetitle compound3-[1-(4-carbamoyl-2-methylphenyl)-5-(4-methanesulfonylaminophenyl)-1H-pyrrol-2-yl]-propionicacid (14C) (19 mg, 82%, yellow powder).

Synthesis of 2,2-dichloroacetaldehyde tosylhydrazone (15A). To anErlenmeyer flask cooled in ice water was added p-toluenesulfonylhydrazide (466 mg, 2.5 mmol) to propionic acid (4 mL).Dichloroacetaldehyde (282 mg, 2.5 mmol) was slowly added. The reactionwas stirred at 0° C. for 30 min, and then warmed to room temperature.After 2 hr, the reaction was cooled to 0° C. for another 2 hr, and thenthe precipitate was collected by filtration and rinsed well withtoluene. The product was dried in vacuo to yield2,2-dichloroacetaldehyde tosylhydrazone (15A) (356 mg, 50%, whitepowder).

Synthesis of3-[1-(4-carbamoyl-2-methylphenyl)-5-(4-[1,2,3]triazol-1-yl-phenyl)-1H-pyrrol-2-yl]-propionicacid ethyl ester (15B). Under a nitrogen atmosphere,3-[5-(4-aminophenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl]-propionicacid ethyl ester (11A, see Scheme 11) (103 mg, 0.26 mmol) was dissolvedin methanol (5 mL). Triethylamine (0.07 mL, 0.48 mmol) was added. Themixture was cooled to 0° C. 2,2-dichloroacetaldehyde tosylhydrazone(15A) (62 mg, 0.22 mmol), dissolved in methanol (1.5 mL) was addedslowly. The reaction was stirred at 0° C. for 5 min, and then heated to40° C. for 3 hrs, then cooled to room temperature for 16 hrs.2,2-dichloroacetaldehyde tosylhydrazone (15A) (62 mg) was added andstirred an additional 4 hr. The reaction was diluted with water (5 mL)and extracted with ethyl acetate. The combined organic layers werewashed with brine, dried over Na₂SO₄, filtered and concentrated invacuo. The crude material was purified by preparative TLC plate (1500microns, 10% IPA/CH₂Cl₂). The desired band (RF=0.3) was isolated anddried under high vacuum to yield3-[1-(4-carbamoyl-2-methylphenyl)-5-(4-[1,2,3]triazol-1-yl-phenyl)-1H-pyrrol-2-yl]-propionicacid ethyl ester (15B) (50 mg, 43%, light tan powder).

Synthesis of3-[1-(4-carbamoyl-2-methylphenyl)-5-(4-[1,2,3]triazol-1-yl-phenyl)-1H-pyrrol-2-yl]-propionicacid (15C).3-[1-(4-carbamoyl-2-methylphenyl)-5-(4-[1,2,3]triazol-1-yl-phenyl)-1H-pyrrol-2-yl]-propionicacid ethyl ester (15B) (50 mg, 0.11 mmol) was hydrolyzed according tothe procedure described above in the final step of scheme 4 to give thetitle compound3-[1-(4-carbamoyl-2-methylphenyl)-5-(4-[1,2,3]triazol-1-yl-phenyl)-1H-pyrrol-2-yl]-propionicacid (15C) (12 mg, 25%, light green powder).

Synthesis of3-[1-(4-Carbamoyl-2-methylphenyl)-5-(4-methoxycarbonyl-methoxyphenyl)-1H-pyrrol-2-yl]-propionicacid ethyl ester (16B).3-[1-(4-Carbamoyl-2-methylphenyl)-5-(4-hydroxyphenyl)-1H-pyrrol-2-yl]-propionicacid ethyl ester 16A (synthesized according to the first three steps ofScheme 1, where Ar2=4-hydroxyphenyl, and Ar1=4-carbamoyl-2-methylphenyl)(47 mg, 0.12 mmol) was dissolved in 0.5 mL N,N-dimethylformamide.Potassium carbonate (33 mg, 0.24 mmol) was added. Methyl 2-bromoacetate(0.02 mL, 0.13 mmol) was added. After 18 hrs, the reaction was pouredinto NH₄Cl (sat) and extracted with EtOAc (2×5 mL). The combined organiclayers were washed with brine and dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by preparative TLC plate(10% IPA/CH₂Cl₂). The desired band (RF=0.57) was isolated and driedunder high vacuum to yield3-[1-(4-Carbamoyl-2-methylphenyl)-5-(4-methoxycarbonyl-methoxyphenyl)-1H-pyrrol-2-yl]-propionicacid ethyl ester (16B) (57 mg, 98%, white powder).

Synthesis of3-[1-(4-Carbamoyl-2-methylphenyl)-5-(4-methoxycarbonyl-methyloxyphenyl)-1H-pyrrol-2-yl]-propionicacid (16C).3-[1-(4-Carbamoyl-2-methylphenyl)-5-(4-methoxycarbonylmethoxy-phenyl)-1H-pyrrol-2-yl]-propionicacid ethyl ester 16B (57 mg, 0.12 mmol) was dissolved in 1 mL methanol.1 N NaOH (0.25 mL, 0.25 mmol.) was added. After 18 hrs, the reaction wasconcentrated in vacuo and diluted with water. The pH was adjusted to 1with 1 M HCl and extracted with EtOAc (3×4 mL). The combined organiclayers were dried over Na₂SO₄, filtered and concentrated in vacuo. Theresidue was triturated with hexanes and dried under high vacuum to yield3-[1-(4-Carbamoyl-2-methylphenyl)-5-(4-methoxycarbonyl-methoxyphenyl)-1H-pyrrol-2-yl]-propionicacid (16C) (34 mg, 65%, light yellow powder).

Synthesis of3-[1-(4-carbamoyl-2-methylphenyl-5-[4-(2-methoxyacetylamino)-phenyl]-1H-pyrrol-2-yl]-propionicacid ethyl ester (17B). Under a nitrogen atmosphere,3-[5-(4-aminophenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl]-propionicacid ethyl ester (11A, see scheme 11) (102 mg, 0.26 mmol), methoxyaceticacid (0.02 mL, 0.31 mmol), and TBTU (167 mg, 0.52 mmol) were dissolvedin 1 mL methylene chloride. Triethylamine (0.11 mL, 0.78 mmol) wasadded. After 24 hrs, the reaction was diluted with water/NaHCO₃ (sat.)(1:1) and extracted with methylene chloride. The combined organic layerswere dried over Na₂SO₄, filtered and concentrated in vacuo. The crudematerial was purified by preparative TLC plate (1500 microns, 10%IPA/CH₂Cl₂). The desired band (rf=0.67) was isolated and dried underhigh vacuum to yield3-{1-(4-carbamoyl-2-methylphenyl-5-[4-(2-methoxyacetylamino)-phenyl]-1H-pyrrol-2-yl}-propionicacid ethyl ester (17B) (80 mg, 66%, yellow solid).

Synthesis of3-{1-(4-carbamoyl-2-methylphenyl-5-[4-(2-methoxyacetylamino)-phenyl]-1H-pyrrol-2-yl}-propionicacid (17C).3-{1-(4-carbamoyl-2-methylphenyl-5-[4-(2-methoxyacetylamino)-phenyl]-1H-pyrrol-2-yl}-propionicacid ethyl ester (17B) (80 mg, 0.17 mmol) was hydrolyzed according tothe procedure described above in the final step of scheme 4, to give thetitle compound3-{1-(4-carbamoyl-2-methylphenyl-5-[4-(2-methoxyacetylamino)-phenyl]-1H-pyrrol-2-yl}-propionicacid (17C) (46 mg, 62%, light yellow powder).

Synthesis of3-{1-(4-carbamoyl-2-methylphenyl)-5-[4-(2-hydroxyacetylamino)-phenyl]-1H-pyrrol-2-yl]-propionicacid ethyl ester (18B). Under a nitrogen atmosphere,3-[5-(4-aminophenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl]-propionicacid ethyl ester (11A, see scheme 11) (102 mg, 0.26 mmol), glycolic acid(40 mg, 0.52 mmol), TBTU (167 mg, 0.52 mmol), and EDC (101 mg, 0.65mmol) were dissolved in 1 mL N, N-dimethylformamide. After 24 hrs, thereaction was diluted with water and extracted with ethyl acetate. Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude material was purified by preparativeTLC plate (1500 microns, 10% IPA/CH₂Cl₂). The desired band (rf=0.25) wasisolated and dried under high vacuum to yield3-{1-(4-carbamoyl-2-methylphenyl)-5-[4-(2-hydroxyacetylamino)-phenyl]-1H-pyrrol-2-yl]-propionicacid ethyl ester (18B) (66 mg, 60%, yellow powder).

Synthesis of3-{1-(4-carbamoyl-2-methylphenyl)-5-[4-(2-hydroxyacetylamino)-phenyl]-1H-pyrrol-2-yl]-propionicacid (18C).3-[1-(4-carbamoyl-2-methylphenyl)-5-[4-(2-hydroxyacetylamino)-phenyl]-1H-pyrrol-2-yl]-propionicacid ethyl ester (18B) (66 mg, 0.16 mmol) was hydrolyzed according tothe procedure described above in the final step of scheme 4, to give thetitle compound3-{1-(4-carbamoyl-2-methylphenyl)-5-[4-(2-hydroxyacetylamino)-phenyl]-1H-pyrrol-2-yl]-propionicacid (18C) (44 mg, 72%, light yellow powder).

Representative Procedure for Scheme 19 Synthesis of3-[5-Benzothiazol-6-yl-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl]-propionicacid (19F, Ar2=benzothiazol-6-yl)

Synthesis of Benzothiazole-6-carbonyl chloride (19A,Ar2=benzothiazol-6-yl). Under a nitrogen atmosphere,benzothiazole-6-carboxylic acid (1.014 g, 5.6 mmol) was dissolved inmethylene chloride (25 mL). Five drops of N,N-dimethylformamide wasadded. Oxalyl chloride (0.5 mL, 5.6 mmol) was slowly added. After 2 hrs,the reaction was heated to 30° C. for 16 hrs. The reaction wasconcentrated in vacuo to yield benzothiazole-6-carbonyl chloride (19A)(1.665 g, quant., light yellow powder).

Synthesis of7-(Benzothiazole-6-carbonyl)-1,4-dioxa-spiro[4.5]decan-8-one (19B,Ar2=benzothiazol-6-yl). Under a nitrogen atmosphere, lithiumhexamethyldisilazide (2.4 mL, 2.4 mmol) was mixed with THF (5 mL). Thereaction was cooled to −78° C. 1,4-cyclohexane-dione monoethylene acetal(374 mg, 2.4 mmol), dissolved in THF (2 mL) was slowly added viadropping funnel. The reaction was stirred for 20 min at −78° C. It wasthen cannulated to a flask, cooled at −78° C., containingbenzothiazole-6-carbonyl chloride (498 mg, 2.52 mmol) dissolved in THF(5 mL). After the addition, the reaction was stirred at −78° C. for 1hr, and then allowed to warm to room temperature. After 12 h, water (30mL) was added and extracted with ethyl acetate (3×20 mL). The combinedorganic layers were washed with 10% citric acid (20 mL), water (20 mL),bicarb (20 mL), and brine (20 mL). It was then dried over Na₂SO₄,filtered and concentrated in vacuo. The crude material was purified bysilica gel column (1:1 EtOAc/Hexanes) to yield7-(Benzothiazole-6-carbonyl)-1,4-dioxa-spiro[4.5]decan-8-one (19B) (271mg, 35%, light yellow solid).

Synthesis of3-[2-(3-Benzothiazol-6-yl-3-oxo-propyl)-[1,3]dioxolan-2-yl]-propionicacid ethyl ester (19C, Ar2=benzothiazol-6-yl). Under a nitrogenatmosphere, 7-(Benzothiazole-6-carbonyl)-1,4-dioxa-spiro[4.5]decan-8-one(271 mg, 0.85 mmol) was dissolved in ethanol (1 mL). 2.43 M sodiumethoxide solution (0.01 mL, 0.03 mmol) was added. After 12 hrs, reactionwas concentrated in vacuo. The residue was diluted with 10 mL EtOAc/5 mL10% citric acid. The layers were separated. The aqueous layer wasfurther extracted with EtOAc (3×3 mL). The combined organic layers werewashed with water (5 mL) and brine (5 mL), dried over Na₂SO₄, filteredand concentrated in vacuo. The crude material was purified by silica gelcolumn (40% EtOAc/hexanes) to yield3-[2-(3-Benzothiazol-6-yl-3-oxo-propyl)-[1,3]dioxolan-2-yl]-propionicacid ethyl ester (19C) (100 mg, 38%, light yellow oil).

Synthesis of 7-Benzothiaol-6-yl-4,7-dioxo-heptanoic acid ethyl ester(19D, Ar2=benzothiazol-6-yl). Under a nitrogen atmosphere,3-[2-(3-Benzothiazol-6-yl-3-oxo-propyl)-[1,3]dioxolan-2-yl]-propionicacid ethyl ester (19C) (100 mg, 0.28 mmol) was dissolved in THF (1 mL).3N HCl was added and stirred at room temperature. After 12 hrs, thereaction was diluted with water and extracted with EtOAc (3 times). Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated in vacuo to give7-Benzothiaol-6-yl-4,7-dioxo-heptanoic acid ethyl ester (19D) (52 mg,58%, dark red solid; ⅔ as ethyl ester, ⅓ as carboxylic acid).

Synthesis of3-[5-Benzothiazol-6-yl-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl]-propionicacid ethyl ester (19E, Ar2=benzothiazol-6-yl). In a 4 mL vial, purgedwith nitrogen, 7-Benzothiaol-6-yl-4,7-dioxo-heptanoic acid ethyl ester(52 mg, 0.16 mmol) was dissolved in 2 mL ethanol. P-toluenesulfonic acid(9.9 mg, 0.05 mmol) and 4-amino-3-methyl benzamide (37 mg, 0.24 mmol)were added. The vial was capped tightly and heated to 80° C. in an oilbath. After the 12 hrs, the reaction was cooled and concentrated invacuo. The crude material was dissolved in N,N-dimethylformamide (1 mL).Potassium carbonate (44 mg, 0.32 mmol) was added. Then iodoethane (0.01mL, 0.17 mmol) was added. The reaction was stirred at room temperaturefor 12 hrs. The reaction was diluted with water and extracted with ethylacetate. The combined organic layers were washed with water, brine anddried over Na₂SO₄, filtered and concentrated in vacuo. The crude productwas purified by silica gel column (5% IPA/CH₂Cl₂) to give3-[5-Benzothiazol-6-yl-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl]-propionicacid ethyl ester (19E, Ar2=benzothiazol-6-yl) (42 mg, 73% over 2 steps,red solid).

Synthesis of3-[5-Benzothiazol-6-yl-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl]-propionicacid (19F, Ar2=benzothiazol-6-yl).3-[5-Benzothiazol-6-yl-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl]-propionicacid ethyl ester (19E) (42 mg, 0.10 mmol) was hydrolyzed according tothe procedure described above in the final step of scheme 4, to give thetitle compound3-[5-Benzothiazol-6-yl-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl]-propionicacid (19F, Ar2=benzothiazol-6-yl) (23 mg, 59%, light tan powder).

Representative Procedure for Scheme 20 Synthesis of3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(2-methyl-4-(methylsulfonamido)phenyl)-1H-pyrrol-2-yl)propanoicacid

Synthesis of3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-amino-2-methylphenyl)-1H-pyrrol-2-yl)propanoicacid (20B, Ar2=4-(1H-imidazol-1-yl)phenyl).3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoicacid (20A, prepared according to Scheme 5,Ar2=4-carbamoyl-2-methylphenyl) (3.88 g, 9.37 mmol) was added to aq.NaOH (4.12 g, 103.09 mmol, dissolving in 50 mL). Then 11% aq. NaClO(28.83 g, 42.17 mmol) was added dropwise. The resulting mixture was keptat 0˜10° C. for 1 h, at 35° C. for 1 h and at 75° C. for 30 min. Aftercooling to room temperature, the reaction was acidified with 10%hydrochloric acid to pH=7.0 and filtered to remove the solid impurity.The filtrate was further acidified with 10% hydrochloric acid to pH=5.0and a new precipitate appeared. The precipitate was filtrated and driedto afford 20B, Ar2=4-(1H-imidazol-1-yl)phenyl as a gray powder (3.20 g,88%).

Synthesis of3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(2-methyl-4-(methylsulfonamido)phenyl)-1H-pyrrol-2-yl)propanoicacid (20C, Ar2=4-(1H-imidazol-1-yl)phenyl). To a solution of pyridine (2mL) and CH₃SO₂Cl/DCM (v/v=1/100, 5 mL) was added a solution of3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-amino-2-methylphenyl)-1H-pyrrol-2-yl)propanoicacid (20B) (250 mg, 0.74 mmol) in pyridine (2 mL) at 0° C. The mixturewas stirred at room temperature for 1 h. The solvents were removed underreduced pressure and the resulting solid was acidified with 10%hydrochloric acid to pH=5.0. The resulting precipitate was isolated bycentrifuge, rinsed with water, dried under reduced pressure to afford20C, Ar2=4-(1H-imidazol-1-yl)phenyl as a brown powder (40 mg, 13%).

Representative procedure for Scheme 21: Synthesis of4-(2-(benzo[d][1,3]dioxol-5-yl)-5-(2-carboxyethyl)-1H-pyrrol-1-yl)-3-methylbenzoicacid. The mixture of ethyl3-(5-(benzo[d][1,3]dioxol-5-yl)-1-(4-cyano-2-methylphenyl)-1H-pyrrol-2-yl)propanoate(prepared by Scheme 6, through intermediate 6F, whereAr2=benzo[d][1,3]dioxol-5-yl) (120 mg, 0.298 mmol) and 20% KOH (2 mL)was heated to 80° C. and stirred for 3 h. TLC and LC-MS showed that thereaction was completed. 10% Hydrochloric acid was added to acidify untilpH=2. The suspension was centrifuged and dried in vacuum to afford4-(2-(benzo[d][1,3]dioxol-5-yl)-5-(2-carboxyethyl)-1H-pyrrol-1-yl)-3-methylbenzoicacid as a white solid (85 mg, 73%).

Synthesis of ethyl3-(5-(4-bromophenyl)-1-(4-cyano-2-methylphenyl)-1H-pyrrol-2-yl)propanoate(22A). 22A was prepared following Scheme 5 through step 5C, whereAr1=4-carbamoyl-2-methylphenyl.

Synthesis of ethyl3-(5-(4-bromophenyl)-1-(4-cyano-2-methylphenyl)-1H-pyrrol-2-yl)propanoate(22B). Ethyl3-(5-(4-bromophenyl)-1-(4-cyano-2-methylphenyl)-1H-pyrrol-2-yl)propanoate(22A) was hydrolyzed according to the procedure described in the finalstep of Scheme 5, to give the title compound.

Synthesis of ethyl3-(1-(4-amino-2-methylphenyl)-5-(4-bromophenyl)-1H-pyrrol-2-yl)propanoate(22C). Ethyl3-(5-(4-bromophenyl)-1-(4-cyano-2-methylphenyl)-1H-pyrrol-2-yl)propanoate(22B) was converted from the nitrile to the amide following the sameprocedure described in Scheme 20, step 1 to give the desired titlecompound, ethyl3-(1-(4-amino-2-methylphenyl)-5-(4-bromophenyl)-1H-pyrrol-2-yl)propanoate(22C).

Synthesis of ethyl3-(1-(4-cyano-2-methylphenyl)-5-(4-(methylthio)phenyl)-1H-pyrrol-2-yl)propanoate(23A). Ethyl3-(1-(4-cyano-2-methylphenyl)-5-(4-(methylthio)phenyl)-1H-pyrrol-2-yl)propanoate23A was prepared following Scheme 6 through 6F, whereAr2=4-(methylthio)phenyl.

Synthesis of ethyl3-(1-(4-cyano-2-methylphenyl)-5-(4-(methylsulfinyl)phenyl)-1H-pyrrol-2-yl)propanoate(23B). To a solution of ethyl3-(1-(4-cyano-2-methylphenyl)-5-(4-(methylthio)phenyl)-1H-pyrrol-2-yl)propanoate(23A) (98 mg, 0.23 mmol) in DCM (1 mL) was added m-CPBA below 0° C. byfive portions. Then the reaction mixture was stirred at room temperaturefor 3 h. TLC showed that the reaction was complete. The mixture wasdiluted with DCM (10 mL) and washed with sat. NaHCO₃ (15 mL), dried overNa₂SO₄, filtered and concentrated to afford a yellow oil, which waspurified by silica gel column chromatography to afford ethyl3-(1-(4-cyano-2-methylphenyl)-5-(4-(methylsulfinyl)phenyl)-1H-pyrrol-2-yl)propanoate(23B) as a light yellow solid (65 mg, 65%).

Synthesis of ethyl3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(methylsulfinyl)phenyl)-1H-pyrrol-2-yl)propanoate(23C). Ethyl3-(1-(4-cyano-2-methylphenyl)-5-(4-(methylsulfinyl)phenyl)-1H-pyrrol-2-yl)propanoate(23B) was converted to the amide following the second to last step ofScheme 6 to give compound ethyl3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(methylsulfinyl)phenyl)-1H-pyrrol-2-yl)propanoate(23C).

Synthesis of3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(methylsulfinyl)phenyl)-1H-pyrrol-2-yl)propanoicacid. Ethyl3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(methylsulfinyl)phenyl)-1H-pyrrol-2-yl)propanoate(23C) was then hydrolyzed following the final step of Scheme 6 to givethe title compound,3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(methylsulfinyl)phenyl)-1H-pyrrol-2-yl)propanoicacid (23D).

Scheme 24 Intentionally Omitted

Representative Procedure for Scheme 25 Synthesis of3-(1-(4-(1H-imidazol-2-yl)-2-methylphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoicacid (25E, Ar1=4-(1H-imidazol-2-yl)-2-methylphenyl)

Synthesis of 3-(furan-2-yl)-1-(4-methoxyphenyl)prop-2-en-1-one (25B). Toa solution of 1-(4-methoxyphenyl)ethanone (17.0 g, 113.0 mmol) inmethanol (240 mL) was added a solution of 2-furaldehyde (12.0 g, 125.0mmol) in methanol (240 mL) followed by the addition of sodium methoxide(6.10 g, 113.0 mmol). The reaction mixture was stirred at roomtemperature for 24 h, and then was neutralized with HCl aq. (6.0 M, 18.8mL). The volatile was removed in vacuum. The residue was dissolved inethyl acetate (500 mL), washed with water (250 mL) and brine (250 mL),dried over Na₂SO₄, filtered, concentrated and purified by silica gelcolumn chromatography (PE:EA=5:1˜3:1) to afford3-(furan-2-yl)-1-(4-methoxyphenyl)prop-2-en-1-one (25B) as a yellowsolid (23.80 g, 92%).

Synthesis of ethyl 7-(4-methoxyphenyl)-4,7-dioxoheptanoate (25C). To asolution of compound 3-(furan-2-yl)-1-(4-methoxyphenyl)prop-2-en-1-one(8.0 g, 35.1 mmol) in ethanol (150 mL) was added conc. HCl (38.0 mL).The resulting mixture was refluxed for 14 h. Then the solution wasneutralized with 10% Na₂CO₃ solution. The volatile was removed. Theresidue was diluted with DCM (750 mL), washed with water (200 mL) andbrine (200 mL), dried over Na₂SO₄, filtered, concentrated and purifiedby silica gel column chromatography (PE:EA=8:1˜4:1) to give ethyl7-(4-methoxyphenyl)-4,7-dioxoheptanoate (25C) as a yellow solid (5.10 g,49%).

Synthesis of ethyl3-(1-(4-(1H-imidazol-2-yl)-2-methylphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoate(25D, Ar1=4-(1H-imidazol-2-yl)-2-methylphenyl). To a solution of4-(1H-imidazol-2-yl)-2-methylaniline (Method #3) (1.0 g, 5.76 mmol) andethyl 7-(4-methoxyphenyl)-4,7-dioxoheptanoate (25C) (2.03 g, 6.93 mmol)in EtOH (12 mL) was added Zn(OTf)₂ (6.30 g, 17.34 mmol). The mixture washeated by microwave at 120° C. for 5 h. The solvent was removed underreduced pressure and the residue was dissolved in EA, washed with waterand brine, dried over MgSO₄, filtered, concentrated and purified bysilica gel column chromatography (PE:EA=1:1) to afford ethyl3-(1-(4-(1H-imidazol-2-yl)-2-methylphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoateas a brown solid (755 mg, 30%).

Synthesis of3-(1-(4-(1H-imidazol-2-yl)-2-methylphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoicacid (25E, Ar1=4-(1H-imidazol-2-yl)-2-methylphenyl). To a solution ofethyl3-(1-(4-(1H-imidazol-2-yl)-2-methylphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoate(100 mg, 0.233 mmol) in THF/H₂O (v/v=1/1, 2 mL) was added lithiumhydroxide monohydrate (15 mg, 0.350 mmol). The solution was stirred atroom temperature overnight. THF was removed under reduced pressure andthe resulting aqueous solution was acidified with 10% hydrochloric acidto pH=6.0. The resulting precipitate was isolated by centrifuge, rinsedwith water, dried under reduced pressure to afford3-(1-(4-(1H-imidazol-2-yl)-2-methylphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoicacid as a brown powder (76 mg, 82%).

Synthesis of3-[1-(4-carbamoyl-2-methyl-phenyl)-5-(4-cyano-phenyl)-1H-pyrrol-2-yl]-propionicacid ethyl ester (26A). 26A was prepared following Scheme 1 through 1C,where Ar1=4-carbamoyl-2-methylphenyl and Ar2=4-cyanophenyl.

Synthesis of3-[1-(4-Carbamoyl-2-methyl-phenyl)-5-[4-(2H-tetrazol-5-yl)-phenyl]-1H-pyrrol-2-yl]-propionicacid ethyl ester (26B). To 25 mL vial which contained3-[1-(4-carbamoyl-2-methyl-phenyl)-5-(4-cyano-phenyl)-1H-pyrrol-2-yl]-propionicacid ethyl ester (26A) (50 mg, 0.12 mmol.) in DMF (4 mL) was addedsodium azide (40 mg, 0.6 mmol.) and ammonium chloride (40 mg, 0.8 mmol.)at rt. The vial was sealed and the reaction mixture was heated to 100°C. and stirred for 16 h. The reaction mixture was cooled to rt andpoured into 30 mL ice-water solution. The aqueous solution was acidifiedwith aq HCl (1 N) to pH=1-2, the solid which formed was filtered out,washed with water (25 mL), dried over air to afford the desired compound3-{1-(4-Carbamoyl-2-methyl-phenyl)-5-[4-(2H-tetrazol-5-yl)-phenyl]-1H-pyrrol-2-yl}-propionicacid ethyl ester (26B) (27 mg, 50% yield).

Synthesis of3-(5-(4-(2H-tetrazol-5-yl)phenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoicacid (26C). To3-{1-(4-carbamoyl-2-methyl-phenyl)-5-[4-(2H-tetrazol-5-yl)-phenyl]-1H-pyrrol-2-yl}-propionicacid ethyl ester (26B) (16 mg, 0.035 mmol.) in 1:1 MeOH/THF (1.0 mL) wasadded aq. 1.0 N lithium hydroxide (2 eq). The reaction mixture wasallowed to stir at rt for 16 h. The reaction mixture was poured into 10mL ice-water solution which was extracted with diethyl ether. Theaqueous layer was acidified with aq HCl (2 N) to pH=2, and then wasextracted with diethyl ether. The combined organic layers were driedover Na₂SO₄. The solvent was removed under vacuum to yield the desiredtarget3-(5-(4-(2H-tetrazol-5-yl)phenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoicacid (26C) (15 mg, 95%).

4-(2-(4-(2H-tetrazol-5-yl)phenyl)-5-(2-carboxyethyl)-1H-pyrrol-1-yl)-3-methylbenzoicacid (26D). To3-{1-(4-carbamoyl-2-methyl-phenyl)-5-[4-(2H-tetrazol-5-yl)-phenyl]-1H-pyrrol-2-yl}-propionicacid ethyl ester 26B (25 mg, 0.055 mmol.) in MeOH (2 mL) was added aq.sodium hydroxide (15%, 0.5 mL). The reaction mixture was allowed to stirat rt for 16 h. The reaction mixture was poured into 20 mL ice-watersolution which was extracted with diethyl ether (2×10 mL). The aqueouslayer was acidified with aq HCl (2 N) to pH=1-2, and then was extractedwith diethyl ether (6×10 mL). The combined organic layers were driedover Na₂SO₄. The solvent was removed under vacuum to yield the desiredtarget4-(2-(4-(2H-tetrazol-5-yl)phenyl)-5-(2-carboxyethyl)-1H-pyrrol-1-yl)-3-methylbenzoicacid (26D) (15 mg, 65%).

Representative Procedure for Scheme 27 Synthesis of3-(1-(4-(Dimethylcarbamoyl)-2-methylphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoicacid (Y=CH₃, X₁=X₂=CH₃)

Synthesis of4-(2-(3-Ethoxy-3-oxopropyl)-5-(4-methoxyphenyl)-1H-pyrrol-1-yl)-3-methylbenzoicacid (27A, Y=CH₃). 4-Amino-3-methylbenzoic acid (0.322 g) was mixed withethyl 7-(4-methoxyphenyl)-4,7-dioxoheptanoate (25C, see scheme 25)(0.498 g) and p-toluenesulfonic acid (49 mg) in dioxane (3 mL). Themixture was heated at 140° C. via microwave over 2 hours. The resultantsolution was diluted with EtOAc (20 mL) and washed with 0.5 N HCl (8mL), Brine (8 mL) and dried over anhydrous Na₂SO₄. After removal ofsolvents under reduced pressure, the residue was purified by flashsilica gel column chromatography, eluted with 10% MeOH in DCM, to afford4-(2-(3-ethoxy-3-oxopropyl)-5-(4-methoxyphenyl)-1H-pyrrol-1-yl)-3-methylbenzoicacid (0.35 g) as a light yellow solid.

Synthesis of Ethyl3-(1-(4-(Dimethylcarbamoyl)-2-methylphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoate(27B, Y=methyl, CH₃, X₁=X₂=CH₃).4-(2-(3-Ethoxy-3-oxopropyl)-5-(4-methoxyphenyl)-1H-pyrrol-1-yl)-3-methylbenzoicacid (44 mg) was treated with TBTU (42 mg), DPPA (10 μL) anddimethylamine HCl (14 mg) in DCM (4 mL) over 8 h at room temperature.The reaction mixture was diluted with EtOAc (15 mL), washed with 0.5 NHCl (8 mL), saturated NaHCO₃ (8 mL), and Brine (8 mL). After removal ofsolvents, the residue was purified by flash silica gel chromatography toafford ethyl3-(5-(4-methoxyphenyl)-1-(2-methyl-4-(methylcarbamoyl)phenyl)-1H-pyrrol-2-yl)propanoate(25 mg).

Synthesis of3-(1-(4-(Dimethylcarbamoyl)-2-methylphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoicacid (27C, Y=methyl, CH₃, X₁=X₂=CH₃). Ethyl3-(5-(4-methoxyphenyl)-1-(2-methyl-4-(methylcarbamoyl)phenyl)-1H-pyrrol-2-yl)propanoate(25 mg) was treated with LiOH.H₂O (6 mg) in THF (3 mL) and H2O (1 mL)over 12 h at room temperature. The basic solution was acidified with 1NH₄Cl and the aqueous layer was extracted with EtOAc (15 mL). Afterremoval of the solvents under reduced pressure, it afforded3-(5-(4-methoxyphenyl)-1-(2-methyl-4-(methylcarba3-(5-(4-Methoxyphenyl)-1-(2-methyl-4-(methylcarbamoyl)phenyl)-1H-pyrrol-2-yl)propanoicacid (20 mg).

Synthesis of ethyl3-(1-(4-cyano-2-methylphenyl)-5-(4-(methylthio)phenyl)-1H-pyrrol-2-yl)propanoate(28A). 28A was prepared following Scheme 6 through 6F, whereAr2=4-(methylthio)phenyl.

Synthesis of ethyl3-(1-(4-cyano-2-methylphenyl)-5-(4-(methylsulfonyl)phenyl)-1H-pyrrol-2-yl)propanoate(28B). To a vigorously stirred solution of ethyl3-(1-(4-cyano-2-methylphenyl)-5-(4-(methylthio)phenyl)-1H-pyrrol-2-yl)propanoate28A (50 mg, 0.12 mmol) in methanol (1 mL) was added dropwise a solutionof oxone (300 mg, 0.74 mmol) in water (5 mL) at 20° C. The mixture wasstirred for 1 h, diluted with water (10 mL) and extracted with ethylacetate (30 mL×3). The combined organic layers were washed with waterand brine, dried over Na₂SO₄, filtered, concentrated and purified bysilica gel flash chromatography (PE:EA=3:1) to afford ethyl3-(1-(4-cyano-2-methylphenyl)-5-(4-(methylsulfonyl)phenyl)-1H-pyrrol-2-yl)propanoate(28B) as a brown solid (120 mg, 37%).

Synthesis of ethyl3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(methylsulfonyl)phenyl)-1H-pyrrol-2-yl)propanoate(28C). To a stirred suspension of ethyl3-(1-(4-cyano-2-methylphenyl)-5-(4-(methylsulfonyl)phenyl)-1H-pyrrol-2-yl)propanoate(28B) (120 mg, 0.28 mmol) and potassium carbonate in DMSO (0.2 mL) wasadded dropwise 30% H₂O₂ at 0° C. The mixture was allowed to warm to roomtemperature and stirred 3 h. After water (2 mL) was added, someprecipitate appeared, which was separated by centrifuge, rinsed withwater (0.5 mL) and dried in vacuum to afford ethyl3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(methylsulfonyl)phenyl)-1H-pyrrol-2-yl)propanoate(28C) as a white solid (100 mg, 80%).

Synthesis of3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(methylsulfonyl)phenyl)-1H-pyrrol-2-yl)propanoicacid (28D). To a solution of ethyl3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(methylsulfonyl)phenyl)-1H-pyrrol-2-yl)propanoate(28C) (100 mg, 0.22 mmol) in THF/H₂O (v/v=1/1, 1 mL) was added lithiumhydroxide monohydrate (18 mg, 0.44 mmol) and stirred overnight at roomtemperature. THF was evaporated in vacuum and the resulting aqueoussolution was acidified with 10% hydrochloric acid to pH=4.0. Theresulting precipitate was separated by centrifuge, rinsed with distilledwater and purified by prep-HPLC to afford3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(methylsulfonyl)phenyl)-1H-pyrrol-2-yl)propanoicacid (28D) as a light green solid (30 mg, 32%).

Representative Procedure for Scheme 29 Synthesis of3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(5-(1H-imidazol-1-yl)pyridin-2-yl)-1H-pyrrol-2-yl)propanoicacid, (29C, R1=5-(1H-imidazol-1-yl)pyridin-2-yl, R2=H)

Synthesis of ethyl 7-(4-bromophenyl)-4,7-dioxoheptanoate (5B). Synthesisof 5B described in scheme 5, steps 1 and 2.

Synthesis of ethyl3-(1-(5-(1H-imidazol-1-yl)pyridin-2-yl)-5-(4-bromophenyl)-1H-pyrrol-2-yl)propanoate(29A, R1=5-(1H-imidazol-1-yl)pyridin-2-yl). To a solution of ethyl7-(4-bromophenyl)-4,7-dioxoheptanoate (5B) (2.56 g, 7.5 mmol) and5-(1H-imidazol-1-yl)pyridin-2-amine (1.20 g, 7.5 mmol) in 15 mL ofethanol was added Zn(OTf)₂ (8.18 g, 22.5 mmol). The resultant mixturewas heated at 120° C. for 4 h under microwave irradiation and thenconcentrated to dryness. The resultant residue was dissolved in EA,washed with water and brine, dried over MgSO₄, concentrated and purifiedby silica gel column chromatography (PE:EA=6:1) to afford ethyl3-(1-(5-(1H-imidazol-1-yl)pyridin-2-yl)-5-(4-bromophenyl)-1H-pyrrol-2-yl)propanoateas a brown oil (250 mg, 7.1%).

Synthesis of ethyl3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(5-(1H-imidazol-1-yl)pyridin-2-yl)-1H-pyrrol-2-yl)propanoate(29B, R1=5-(1H-imidazol-1-yl)pyridin-2-yl, R2=H). To a mixture of ethyl3-(1-(5-(1H-imidazol-1-yl)pyridin-2-yl)-5-(4-bromophenyl)-1H-pyrrol-2-yl)propanoate(29A) (200 mg, 0.43 mmol) and imidazole (35 mg, 0.516 mmol) in DMSO (5mL) was added L-proline (19.8 mg, 0.172 mmol), CuI (16.4 mg, 0.086 mmol)and K₂CO₃ (119 mg, 0.86 mmol). The resultant mixture was heated at 150°C. for 5 h under microwave irradiation, poured into water and extractedwith EA for 5 times. The combined organic layers were washed with brine,dried over MgSO₄, concentrated and purified by silica gel columnchromatography (DCM:MeOH=20:1) to afford ethyl3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(5-(1H-imidazol-1-yl)pyridin-2-yl)-1H-pyrrol-2-yl)propanoateas a brown oil (40 mg, 21%).

Synthesis of3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(5-(1H-imidazol-1-yl)pyridin-2-yl)-1H-pyrrol-2-yl)propanoicacid (29C, R1=5-(1H-imidazol-1-yl)pyridin-2-yl, R2=H). To a solution ofethyl3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(5-(1H-imidazol-1-yl)pyridin-2-yl)-1H-pyrrol-2-yl)propanoate(29B) (40 mg, 0.088 mmol) in THF/H₂O (v/v=1/1, 2 mL) was added LiOH H₂O(11 mg, 0.264 mmol). The solution was stirred at room temperature for 8h. THF was removed under reduced pressure and the resultant aqueoussolution was acidified with 10% hydrochloric acid to pH=5. The resultantprecipitate was isolated by centrifuge, rinsed with water, dried invacuo to afford3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(5-(1H-imidazol-1-yl)pyridin-2-yl)-1H-pyrrol-2-yl)propanoicacid (12 mg, yield 32%) as a yellow powder.

Synthesis of ethyl3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoate(30A). 30A was prepared following the first four steps of Scheme 5,where Ar1=4-carbamoyl-2-methylphenyl.

Synthesis of ethyl3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-cyano-2-methylphenyl)-1H-pyrrol-2-yl)propanoate(30B). To a solution of ethyl3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoate(30A) (2.0 g, 4.52 mmol) in DMF (9 mL) was added POCl₃ (693 mg, 4.52mmol) at 0° C., and then stirred at room temperature for 1.5 h. Aftercooling to room temperature, the reaction mixture was added to ice-water(20 mL). Sat. Na₂CO₃ was added to adjust pH=8 followed by extractionwith ethyl acetate (50 mL×4). The combined organic layers were driedover Na₂SO₄, filtered, concentrated and purified by silica gel columnchromatography (PE:EA=1:1) to afford ethyl3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-cyano-2-methylphenyl)-1H-pyrrol-2-yl)propanoate(30B) (1.02 g, 53%), LC-MS: [M+H]⁺ 425.

Synthesis of ethyl3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-(aminomethyl)-2-methylphenyl)-1H-pyrrol-2-yl)propanoate(30C). To a solution of ethyl3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-cyano-2-methylphenyl)-1H-pyrrol-2-yl)propanoate(30B) (300 mg, 0.71 mmol) in methanol (10 mL) was added CoCl₂.6H₂O (337mg, 1.41 mmol), then NaBH₄ (137 mg, 3.53 mmol) was added in portionswithin 30 min. The reaction mixture was stirred at room temperature for2 h. 10% hydrochloric acid was added to adjust pH=2. After methanol wasdistilled, conc. NH₃.H₂O was added to adjust pH=8 followed by extractionwith ethyl acetate (80 mL×3). The combined organic layers were driedover Na₂SO₄, filtered and concentrated to afford crude ethyl3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-(aminomethyl)-2-methylphenyl)-1H-pyrrol-2-yl)propanoate(30C) (300 mg), which was used for the next step without furtherpurification. LC-MS: [M+H]⁺ 428.

Synthesis of3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-(aminomethyl)-2-methylphenyl)-1H-pyrrol-2-yl)propanoicacid (30D). To a solution of ethyl3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-(aminomethyl)-2-methylphenyl)-1H-pyrrol-2-yl)propanoate(30C) (300 mg) in THF/H₂O (v/v=1/1, 6 mL) was added lithium hydroxidemonohydrate (50.4 mg, 2.10 mmol). The solution was stirred at roomtemperature overnight. THF was removed under reduced pressure and theresulting solution was acidified with 10% hydrochloric acid to pH=6.0.The resulting precipitate was isolated by centrifuge, rinsed with water,dried under reduced pressure and purified by prep-HPLC to afford3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-(aminomethyl)-2-methylphenyl)-1H-pyrrol-2-yl)propanoicacid (30D) (170 mg, 74%) as a yellow solid.

Representative procedure for Scheme 31: Synthesis of3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(2-methyl-4-propionamidophenyl)-1H-pyrrol-2-yl)propanoicacid (R1=H, R2=ethyl). To a solution of pyridine (1 mL) and C₂H₅COCl/DCM(v/v=1/100, 4.2 mL) was added a solution of 20B (see scheme 20) (150 mg,0.389 mmol) in pyridine (1 mL) at 0° C. The mixture was stirred at roomtemperature overnight. The solvents were removed under reduced pressureand the resulting solid was acidified with 10% hydrochloric acid topH=5.0. The resulting precipitate was isolated by centrifuge, rinsedwith water, dried under reduced pressure to afford the crude product asa brown powder, After purification by prep-HPLC,3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(2-methyl-4-propionamidophenyl)-1H-pyrrol-2-yl)propanoicacid (32 mg, 19%) was obtained as a brown oil.

Synthesis of Compound 32C. To a mixture of 32A (200 mg, 0.49 mmol) andpyridazin-4-amine (56 mg, 0.59 mmol) in THF (3 mL) was added DCC (152mg, 0.74 mmol) and the mixture was stirred at room temperatureovernight. TLC showed the reaction was complete. Water (5 mL) was addedand the mixture was extracted with ethyl acetate (5 mL×4). The combinedorganic layers were dried over Na₂SO₄, filtered, concentrated andpurified by silica gel column chromatography (DCM:MeOH=15:1) to afford32C as a yellow solid (137 mg, yield 58%).

Synthesis of Compound 32D. Hydrolysis of 32C completed followingprocedure described in the last step of Scheme 5.

Representative Procedure for Scheme 33 Synthesis of3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-chloro-2-methoxyphenyl)-1H-pyrrol-2-yl)propanoicacid (33C, R1=4-carbamoyl-2-methylphenyl, R2=4-chloro, R3=methyl)

Synthesis of 33A, R1=4-carbamoyl-2-methylphenyl, R2=4-chloro. Preparedfollowing scheme 1 thru 1C, R1=4-carbamoyl-2-methylphenyl,R2=4-chloro-2-hydroxyphenyl.

Synthesis of 33B, R1=4-carbamoyl-2-methylphenyl, R2=4-chloro, R3=methyl.33A (300 mg, 0.704 mmol) was dissolved in acetone. Potassium carbonate(146 mg, 1.056 mmol) and methyl iodide (299 mg, 2.112 mmol) was addedand stirred at room temperature overnight. When TLC indicated that thereaction was complete, the mixture was filtered, evaporated in vacuo.The residue was partitioned between ethyl acetate (20 mL) and water (5mL). The organic phase was dried with magnesium sulfate, filtered andconcentrated to afford 33B (R1=4-carbamoyl-2-methylphenyl, R2=4-chloro,R3=methyl) as a yellow oil (295 mg, yield 95%).

Synthesis of3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-chloro-2-methoxyphenyl)-1H-pyrrol-2-yl)propanoicacid (33C, R1=4-carbamoyl-2-methylphenyl, R2=4-chloro, R3=methyl).Hydrolysis completed following final step of Scheme 5.

Representative Procedure for Scheme 34 Synthesis of3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(2-cyclopropyl-1H-imidazol-1-yl)phenyl)-1H-pyrrol-2-yl)propanoicacid (34C, Ar1-X=4-bromophenyl, Art is 2-cyclopropyl-1H-imidazol-1-yl,R1=4-carbamoyl-2-methylphenyl)

Synthesis of ethyl3-(5-(4-bromophenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoate(34A, R1=4-carbamoyl-2-methylphenyl, Ar1-X=4-bromophenyl). Prepared byScheme 1 through step 1C.

Synthesis of ethyl3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(2-cyclopropyl-1H-imidazol-1-yl)phenyl)-1H-pyrrol-2-yl)propanoate(34B, Ar1-X=4-bromophenyl, Ar2 is 2-cyclopropyl-1H-imidazol-1-yl,R1=4-carbamoyl-2-methylphenyl. To a mixture of 34A (Ar2=4-bromophenyl)(455 mg, 1.0 mmol) and 2-cyclopropyl-1H-imidazole (see Method 14 forsynthesis) (324 mg, 3.0 mmol, 3.0 eq) in NMP (4 mL) was added8-hydroxyquinoline (22 mg, 0.15 mmol, 0.15 eq), Cu₂O (282 mg, 0.1 mmol)and K₂CO₃ (166 mg, 1.2 mmol) and PEG-2000 (50 mg). The resultant mixtureunder N₂ was irradiated under microwave at 128° C. for 6.0 h, cooled toroom temperature and diluted with THF (10 mL) and water (10 mL). Themixture was filtered and the resultant aqueous layer was extracted withEA (30 mL×5). The combined organic layers were washed with brine (20mL), dried over MgSO₄, filtered, concentrated and purified by silica gelcolumn chromatography (MeOH:CH₂Cl₂=1:15) to afford the desired compoundas a yellow solid (190 mg, yield 39%).

Synthesis of3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(2-cyclopropyl-1H-imidazol-1-yl)phenyl)-1H-pyrrol-2-yl)propanoicacid (34C, Ar1-X=4-bromophenyl, Ar2 is 2-cyclopropyl-1H-imidazol-1-yl,R1=4-carbamoyl-2-methylphenyl). Hydrolysis completed following finalstep of Scheme 5 to give the title compound.

Synthesis of Compound 35-2. To a solution of NaOH (5.10 g, 127.6 mmol)in water (300 mL) was added 35-1 (20.0 g, 121.6 mmol). After the solidof 35-1 was dissolved, 2-furaldehyde (11.72 g, 121.6 mmol) was added andthe mixture was stirred at room temperature for 4 h, then the resultantsolid was filtered, washed with water (20 mL×2), suspended in water (120mL) and acidified to pH=3 with 10% hydrochloric acid, extracted with EA(160 mL×3). The combined organic layers were dried over Na₂SO₄, filteredand concentrated to afford 35-2 as a yellow solid (21.65 g, yield 73%).

Synthesis of Compound 35-3. To a solution of compound 35-2 (11.40 g,47.1 mmol) in ethanol (100 mL) was added conc. HBr (30 mL). Theresultant mixture was refluxed for 14 h. Ethanol was evaporated in vacuoand the residue was extracted with ethyl acetate (80 mL×4). The combinedorganic layers were washed with sat. NaHCO₃ (100 mL) and brine (80 mL),dried over Na₂SO₄, filtered, concentrated and purified by silica gelcolumn chromatography (PE:EA=10:1) to afford 35-3 as a yellow solid(1.40 g, yield 20%).

Synthesis of Compound 35-4. To a solution of compound B35-3 (1.845 g,5.52 mmol) in anhydrous ethanol (20 mL) was added4-amino-3-methylbenzamide (0.91 g, 6.06 mmol) and TsOH (211 mg, 1.11mmol) and the mixture was heated under reflux overnight. TLC and LC-MSshowed that the reaction was complete. Ethanol was evaporated in vacuoand the residue was purified by silica gel column chromatography(PE:EA=8:1) to afford 35-4 as a yellow solid (1.69 g, yield 70%).

Synthesis of4-(1-(4-carbamoyl-2-methylphenyl)-5-(2-carboxyethyl)-1H-pyrrol-2-yl)benzoicacid (Compound 35-5). To a mixture of compound B30-4 (140 mg, 0.31 mmol)in THF/H₂O/MeOH (5 mL, v/v=2/2/1) was added lithium hydroxidemonohydrate (65 mg, 1.56 mmol). The mixture was stirred at roomtemperature overnight. THF was evaporated in vacuo. The residue wasacidified to pH=3 with 10% hydrochloric acid. The resultant precipitatewas isolated by centrifuge and purified by prep-HPLC to afford 35-5 as awhite powder (70 mg, yield 56%).

Synthesis of Compound 35-6. To the mixture of compound 35-5 (500 mg,1.12 mmol) in THF/H₂O/MeOH (10 mL, v/v/v=5/4/1) was added lithiumhydroxide monohydrate (49 mg, 1.17 mmol). The mixture was stirred atroom temperature overnight. THF was evaporated in vacuo. The residue wasacidified to pH=4 with 5% hydrochloric acid, filtered and dried in vacuoto afford 35-6 as a white solid (469 mg, yield 100%).

Synthesis of3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(hydroxycarbamoyl)phenyl)-1H-pyrrol-2-yl)propanoicacid (Compound 35-7). To a mixture of compound 35-6 (469 mg, 1.12 mmol)in 1M hydroxylammonium methanol solution (11.2 mL, 11.2 mmol) was addedpotassium hydroxide (150 mg, 2.23 mmol). The mixture was stirred at 0°C. for 4 h and concentrated. The residue was dissolved in water (10 mL)and acidified to pH=4 with 10% hydrochloric acid. The resultantprecipitate was isolated by centrifuge and purified by prep-HPLC toafford 35-7 as a white powder (130 mg, yield 29%).

Representative Procedure for Scheme 363-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(2-oxooxazolidin-3-yl)phenyl)-1H-pyrrol-2-yl)propanoicacid

Synthesis of ethyl4,7-dioxo-7-(4-(2-oxooxazolidin-3-yl)phenyl)heptanoate. To a mixture ofethyl 7-(4-bromophenyl)-4,7-dioxoheptanoate ((36A, whereAr1-Br=4-bromophenyl, also see compound 5B, Scheme 5) (1.50 g, 4.4 mmol)and oxazolidin-2-one (575 mg, 6.6 mmol) in dioxane (5 mL) were addedL-proline (50 mg, 0.44 mmol), CuI (42 mg, 0.22 mmol) and K₂CO₃ (1.22 g,8.8 mmol). The resultant mixture was stirred under N₂ at 110° C. for 48h and then evaporated. The residue was diluted with EA/water (40 mL/40mL). The mixture was filtered and the resultant aqueous layer wasextracted with EA (30 mL×5). The combined organic layers were washedwith brine, dried over NaSO₄, concentrated and purified by silica gelcolumn chromatography (pure DCM to DCM:MeOH=30:1) to afford titledcompound as a white solid (158 mg, yield 10%).

Synthesis of ethyl3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(2-oxooxazolidin-3-yl)phenyl)-1H-pyrrol-2-yl)propanoate.To a solution of ethyl4,7-dioxo-7-(4-(2-oxooxazolidin-3-yl)phenyl)heptanoate (158 mg, 0.43mmol) and 4-amino-3-methylbenzamide (130 mg, 0.68 mmol) in EtOH (1 mL)was added Zn(OTf)₂ (313 mg, 0.86 mmol.). The mixture was heated to 120°C. under microwave for 2 h. After evaporation under reduced pressure,the crude product was purified by silica gel column chromatography(DCM:MeOH=20:1) to afford the titled compound as a yellow solid (77 mg,yield 39%).

Synthesis of3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(2-oxooxazolidin-3-yl)phenyl)-1H-pyrrol-2-yl)propanoicacid. To a solution of ethyl3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(2-oxooxazolidin-3-yl)phenyl)-1H-pyrrol-2-yl)propanoate(67 mg, 0.15 mmol) in THF/H₂O (1 mL, v/v=1/1) was added lithiumhydroxide monohydrate (7 mg, 0.15 mmol). The mixture was stirred at roomtemperature for 6 h. THF was evaporated in vacuo. The residue wasacidified to pH=5 with 5% hydrochloric acid, concentrated and purifiedby prep-TLC to afford the titled compound as a brown solid (24 mg, yield39%).

Representative procedure for Scheme 36A: Synthesis of ethyl7-(3-fluoro-4-(1H-imidazol-1-yl)phenyl)-4,7-dioxoheptanoate (R=H). Ethyl7-(3,4-difluorophenyl)-4,7-dioxoheptanoate (351 mg) was treated withimidazole (241 mg) and pyridine (395 mg) in DMSO (3 mL) at 150° C. over7 h with a micro-wave heating. The resultant mixture was diluted withwater (12 mL) and was extracted with EtOAc (20 mL×3). After removal thesolvents, the mixture was purified by flash silica gel chromatography,eluting with EtOAc, to afford the desired product -ethyl7-(3-fluoro-4-(1H-imidazol-1-yl)phenyl)-4,7-dioxoheptanoate (279 mg,68%) as light brown solids.

Representative procedure for Scheme 36B: Synthesis of ethyl7-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-4,7-dioxoheptanoate. Ethyl7-(4-fluorophenyl)-4,7-dioxoheptanoate (2.00 g, 7.1 mmol) and2-methyl-1H-imidazole (7.0 g, 86 mmol) were taken up into DMSO (4 mL).The mixture was heated to 180° C. under microwave for 72 min. Water (100mL) was added and the mixture was extracted with ethyl acetate (50mL×3). The combined organic layers were washed with brine (40 mL), driedover Na₂SO₄, filtered, concentrated and purified by silica gel columnchromatography (DCM to DCM:MeOH=25:1) to afford the title compound as adark brown solid (660 mg, yield 25%).

Step 1: Synthesis of 4-(4-bromophenyl)-4-oxobutanoic acid (37A, R=Br).Anhydrous aluminum trichloride (29.1 g, 218 mmol) was suspended indichloromethane (120 mL) and cooled to 0° C. Bromobenzene (35.1 g, 224mmol) was added carefully. When the addition was complete, succinicanhydride (10.0 g, 100 mmol) was added in ten portions carefully. Thenthe mixture was warmed to room temperature and stirred for 4 h. TLCshowed the reaction was complete, 6N HCl (50 mL) was added dropwise. Thesolid was filtered, washed with distilled water (10 mL×2) and dried invacuo to afford 37A, R=Br as a white solid (22 g, yield 82%).

Step 2 and 3: Synthesis of1-(4-bromophenyl)-4-(1H-imidazol-1-yl)butane-1,4-dione (37C, R=Br). To asolution of 37A, R=Br (5.00 g, 18.6 mmol) in anhydrous MeCN (50 mL) wasadded CDI (3.91 g, 24.2 mmol). The solution was stirred at roomtemperature for 2 h and turned red to give 37B, R=Br, which was used forthe next step without any purification. To a suspension of potassium3-ethoxy-3-oxopropanoate (6.32 g, 37.2 mmol) in anhydrous MeCN (200 mL)TEA (5.63 g, 55.8 mmol) and anhydrous magnesium dichloride (5.3 g, 55.8mmol) was added gradually at 0° C. The mixture was stirred at roomtemperature for 2 h, to which the solution of 37B, R=Br was added inportions. The mixture was stirred at room temperature overnight. Thevolatiles were removed under reduced pressure and the residue wasdissolved in EA (250 mL), washed with water (50 mL×2) and brine (30 mL),dried over Na₂SO₄, filtered, concentrated and purified by silica gelcolumn chromatography (PE:EA=3:1) to afford ethyl6-(4-bromophenyl)-3,6-dioxohexanoate (37C, R=Br) as a brown solid (5.3g, yield 88%).

Step 4: Synthesis of ethyl2-(5-(4-bromophenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)acetate(37D, R=Br, Ar1=4-carbamoyl-2-methylphenyl). 37C, R=Br was cyclizedfollowing step 3 of Scheme 1 with 4-amino-3-methylbenzamide with adifferent solvent, dioxane.

Step 5: Synthesis of ethyl2-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(thiophen-3-yl)phenyl)-1H-pyrrol-2-yl)acetate(37E, R=Br, Ar1=4-carbamoyl-2-methylphenyl). Coupling with 37D, R=Br,Ar1=4-carbamoyl-2-methylphenyl and thiophen-3-ylboronic acid wasperformed under conditions described in Scheme 6, step 6 to give 37E,R=Br, Ar1=4-carbamoyl-2-methylphenyl.

Step 6: Synthesis of2-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(thiophen-3-yl)phenyl)-1H-pyrrol-2-yl)aceticacid (37F, R=Br, Ar1=4-carbamoyl-2-methylphenyl). Hydrolysis of 37E wasperformed following the final step of Scheme 5 to give the desiredcompound, 37F, R=Br, Ar1=4-carbamoyl-2-methylphenyl.

Representative Procedure for Scheme 38 Synthesis of3-(5-(5-bromofuran-2-yl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoicacid

Synthesis of 5-bromofuran-2-carbonyl chloride. At 0° C., to a stirredsolution of 5-bromofuran-2-carboxylic acid (3.00 g, 15.7 mmol) in DCM(30 mL) was added dropwise oxalyl dichloride (4.50 mL, 47.1 mmol). Thenthe resulted mixture was stirred at room temperature for 2 h. TLC andLC-MS showed no starting material. The volatile was removed underreduced pressure and the residual yellow solid was used without furtherpurification (3.20 g, quant.)

Synthesis of 7-(5-bromofuran-2-carbonyl)-1,4-dioxaspiro[4.5]decan-8-one.Under N₂ at about −35° C., to a stirred solution of 1,4-cyclohexanedionemonoethyleneacetal (2.57 g, 16.5 mmol) in THF (30 mL) was added asolution of LHMDS (20% in THF, 18 mL, 18.8 mmol) over about 1 h. Afterstirred for another 1 h, the resulted solution was added dropwise to thesolution of 5-bromofuran-2-carbonyl chloride (3.20 g, 15.7 mmol) in THF(30 mL) at about −35° C. over about 0.5 h and then stirred withoutcooling for about 1 h. NaOH solution (2.51 g in 300 mL of water, 62.8mmol) was added to the above solution, and the resultant mixture washeated under reflux for a further 0.5 h. The volatile was removed underreduced pressure and then the aqueous phase was acidified with 6N HCl topH=5 at 0-10° C. and filtered. The collected solids were dried in vacuoand then recrystallized from ethanol to give7-(5-bromofuran-2-carbonyl)-1,4-dioxaspiro[4.5]decan-8-one as a yellowsolid (2.02 g, 36%), which was used without further purification.

Synthesis of3-(2-(3-(5-bromofuran-2-yl)-3-oxopropyl)-1,3-dioxolan-2-yl)propanoicacid. 7-(5-bromofuran-2-carbonyl)-1,4-dioxaspiro[4.5]decan-8-one. (2.00g, 5.78 mmol), 4-amino-3-methylbenzamide (1.04 mg, 6.90 mmol) and TsOH(100 mg, 0.578 mmol) were taken up into EtOH (20 mL). The resultedmixture was heated to reflux for 61 h. After evaporation under reducedpressure, the crude product was purified by a silica gel columnchromatography (EA:PE=1:1) to afford3-(2-(3-(5-bromofuran-2-yl)-3-oxopropyl)-1,3-dioxolan-2-yl)propanoicacid as a yellow solid (760 mg, yield: 30%).

Synthesis of3-(5-(5-bromofuran-2-yl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoicacid. To a solution of3-(2-(3-(5-bromofuran-2-yl)-3-oxopropyl)-1,3-dioxolan-2-yl)propanoicacid (100 mg, 0.224 mmol) in THF/H₂O (v/v=2/1, 1.5 mL) was added lithiumhydroxide monohydrate (19 mg, 0.449 mmol). The solution was stirred atroom temperature for 8 h. THF was removed under reduced pressure and theresultant aqueous solution was purified by Prep-HPLC to afford3-(5-(5-bromofuran-2-yl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoicacid as a grey solid (45 mg, yield: 48%).

Synthesis of 39a-A. To a mixture of 16-4 (Method 16) (200 mg, 0.419mmol) in acetone (5 mL) was added MeI (118 mg, 0.838 mmol). DMF (5 mL)was added after stirred at rt overnight. The mixture was heated to 30°C. overnight. The solution was concentrated and diluted with water (15mL), extracted with ethyl acetate (10 mL×4). The organic phase wasseparated and dried, purified with prep-TLC (PE:EA=1:1) to afford 39a-Aas a yellow oil (104 mg, 51%).

Synthesis of 39a-B. Followed the procedure described in the last twosteps of Scheme 6 (steps 7 and 8), with a purification of the finalproduct by prep-HPLC.

Synthesis of 39b-A. To a mixture of 16-4 (Method 16) (200 mg, 0.419mmol), NaBH₃CN (53 mg, 0.838 mmol), 37% HCHO (1.5 mL, 2.095 mmol) inCH₃CN (5 mL) was added AcOH (0.5 mL). After stirred at rt overnight, thesolution was concentrated and diluted with water (15 mL), extracted withethyl acetate (10 mL×4). The organic phase was separated and dried,purified with prep-TLC (PE:EA=1:1) to afford 39b-A as a yellow oil (97mg, 49%).

Synthesis of 39b-B. Followed the procedure described in the last twosteps of Scheme 6 (steps 7 and 8), with a purification of the finalproduct by prep-HPLC.

Synthesis of 40A: See method described in Scheme 31.

Synthesis of 40B: See methodology described in the last steps of Scheme6 (steps 7 and 8).

Compound 41A. A solution of 5C (900 mg, 2 mmol), Bis(pinacolato)diboron(609 mg, 2.4 mmol), KOAc (344 mg, 4 mmol) and Pd(dppf)₂Cl₂DCM (326 mg,0.4 mmol) in dioxane/H₂O (v/v=9/1) was stirred at 100° C. overnight. TLCshowed that the reaction was complete. The mixture was evaporated toafford a brown oil. Water (6 mL) was added and the mixture was extractedwith ethyl acetate (10 mL×3). The combined organic layers were driedover MgSO₄, filtered, concentrated and purified by silica gel columnchromatography (PE:EA=1:1) to afford 41A as a yellow oil (730 mg, 73%).

Compound 41B. To a suspension of 41A (1.00 equivalent), 5-bromothiazole(0.92 equivalent), and sodium bicarbonate (3.15 equivalents) in solvents(DME/H₂O/Toluene/EtOH=10/1/6/3, 4 mL) was added Pd(PPh₃)₄ (0.2equivalents). The reaction was degassed, purged with nitrogen and heatedto reflux for 5 h. TLC showed that the reaction was complete. Water (4mL) was added and the mixture was extracted with ethyl acetate (5 mL×3).The combined organic layers were dried over MgSO₄, filtered,concentrated and purified by silica gel column chromatography(DCM:MeOH=15:1) to afford 41B as a colorless oil.

Synthesis of 42A. Follow scheme 6 through 6F, whereAr2=2-methoxypyrimidin-5-yl, using the boronic acid intermediatedescribed in Method 11.

Synthesis of 42B. To a solution of 42A (500 mg, 1.03 mmol) in toluene (5mL) was added POCl₃ (0.3 mL, 6.0 mmol) at 0° C., and then stirred at 90°C. overnight. After cooling to room temperature, the reaction mixturewas added to ice-water (20 mL). Sat. Na₂CO₃ was added to adjust pH=7 andextracted with ethyl acetate (50 mL×4). The combined organic layers weredried over Na₂SO₄, filtered, concentrated and purified by silica gelcolumn chromatography (PE:EA=3:1) to afford 42B as a yellow solid (145mg, 30%).

Synthesis of 42C. Followed the coupling procedure described in Scheme 5with the conversion of 5C to 5D.

Synthesis of 42D. Followed the final two steps of Scheme 6, (6F to 6H)to give the desired compound,3-(5-(2-(1H-imidazol-1-yl)pyrimidin-5-yl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoicacid.

Synthesis of Compound 43B. 43A (500 mg, 1.23 mmol) was dissolved in DMF(7 mL). EDCI (592 mg, 1.85 mmol) and HOBT (250 mg, 1.85 mmol) were addedand stirred the resultant mixture was stirred at 50° C. for 1 h.Pyridin-4-amine (121 mg, 1.29 mmol) was then added. After continualagitation at 50° C. overnight, brine (30 mL) was added and the resultantmixture was extracted with ethyl acetate (30 mL×3). The organic phasewas washed with sat. NaHCO₃ (20 mL×2) and brine (20 mL), dried overMgSO₄, concentrated and purified by prep-TLC (MeOH:dichloromethane=1:15)to afford 43B as a yellow solid (243 mg, yield 41%).

Synthesis of Compound 43C. Hydrolysis of 43B completed followingprocedure described in the last step of Scheme 5.

An 8 ml vial was loaded with a mixture of 30% H₂O₂ (50 uL), 3N NaOH(0.15 ml) and MeOH (0.125 ml). To this mixture3-[1-(3-chloro-4-cyanophenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl]propanoicacid (40 mg, 0.105 mmol) was added at room temperature. The reactionmixture was stirred at rt for 45 minutes, TLC showed the startingmaterial to be consumed. The reaction mixture was diluted with water,acidified to pH=2, stirred for 10 minutes, and filtered off. The solidwas washed with water and dried to give 30 mg of3-(1-(4-carbamoyl-3-chlorophenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoicacid, 73% yield.

Representative procedure for Scheme 45: Synthesis of3-(1-(4-acetylphenyl)-5-phenyl-1H-pyrrol-2-yl)propanoic acid (45-2,R2=H, R1=4-acetylphenyl). To a mixture of 4,7-dioxo-7-phenyl-heptanoicacid (150 mg, 0.64 mmol) in acetic acid (1.5 mL) was added4-amino-acetophenone (87 mg, 0.64 mmol). The reaction was run usingMicrowave Biotage Initiator for 1 hour at 150° C. The solvent wasremoved in vacuo to provide the crude mixture, which was washed withwater and filtered off. The solid was triturated with ether/methanol(98/2) to give 150 mg of3-(1-(4-acetylphenyl)-5-phenyl-1H-pyrrol-2-yl)propanoic acid (45-2,R2=H, R1=4-acetylphenyl), 70% yield.

To a solution of3-(1-(4-hydroxy-3-(methoxycarbonyl)phenyl)-5-phenyl-1H-pyrrol-2-yl)propanoicacid (40 mg, 0.109 mmol) in 2 ml anhydrous THF was added LiBH₄ (2M inTHF, 0.14 ml, 2.5 eq.) via a syringe at 0° C. The reaction mixture wasstirred at rt for 4 hours. Mixture was quenched with saturated sol.NH₄Cl, then acidified to pH=2 using 10% HCl solution. This was extractedseveral times using ethyl acetate. Combined organic layers were washedwith brine, dried (Na₂SO₄) and concentrated. The crude was purified bypreparative TLC using 1:1 ethyl acetate/hexane. 18 mg of3-(1-(4-hydroxy-3-(hydroxymethyl)phenyl)-5-phenyl-1H-pyrrol-2-yl)propanoicacid was obtained, 47% yield.

Synthesis of ethyl3-(1-(4-cyano-3-fluorophenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoate(47-1). Followed procedure described in Scheme 1, step 3.

Synthesis of ethyl3-(1-(3-aminobenzo[d]isoxazol-6-yl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoate(47-2). In 4 mL of dry DMF was dissolved acetohydroxamic acid (57 mg,0.765 mmol), followed by potassium t-butoxide (86 mg, 0.765 mmol) atambient temperature. After this mixture had been stirred for 30 min,compound 47-1 (200 mg, 0.510 mmol) was added and stirred overnight. Thereaction mixture was poured into a mixture of brine (30 mL) and ethylacetate (30 mL). The organic phase was separated, the aqueous layer wasextracted EA (20 mL×3). The combined organic phase was washed with brine(30 mL), dried over anhydrous Na₂SO₄, filtered, concentrated andpurified by silica gel column chromatography (PE:EA=1:1) to afford 47-2as a yellow oil (80 mg, 39%).

Synthesis of3-(1-(3-aminobenzo[d]isoxazol-6-yl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoicacid (47-3). Followed procedure described in the last step of Scheme 25to get the desired product, 47-3.

Representative Procedure for Scheme 48 Synthesis of3-(5-(4-methoxyphenyl)-1-(4-(pyridin-3-ylamino)phenyl)-1H-pyrrol-2-yl)propanoicacid (48-3, R2=H, R1=4-acetylphenyl)

Synthesis of ethyl3-(1-(4-bromophenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoate(48A). Prepared by Scheme 1, Step 1-Step 3, where R1=4-bromophenyl,R2=4-methoxy phenyl.

Synthesis of ethyl3-(5-(4-methoxyphenyl)-1-(4-(pyridin-3-ylamino)phenyl)-1H-pyrrol-2-yl)propanoate(48B, R=pyridin-3-yl). 48A (500 mg, 1.17 mmol), pyridin-3-amine (121 mg,1.28 mmol), Pd₂(dba)₃ (54 mg, 0.0600 mmol), XPhos (42 mg, 0.0870 mmol)and K₂CO₃ (485 mg, 3.50 mmol) were taken up into dioxane (4 mL). Afterbeing degassed and refilled with nitrogen, the resulted mixture washeated to 100° C. under microwave for 3 h. After evaporation underreduced pressure, the crude product was purified by silica gel columnchromatography (MeOH:DCM=1:10) to afford 48B, R=pyridin-3-yl as a yellowoil (344 mg, yield: 44%).

Synthesis of3-(5-(4-methoxyphenyl)-1-(4-(pyridin-3-ylamino)phenyl)-1H-pyrrol-2-yl)propanoicacid (48C, R=pyridin-3-yl). Followed procedure described in the finalstep of Scheme 5 to give 48C, R=pyridin-3-yl as a white solid (45 mg,yield: 14%).

To a solution of ethyl3-(5-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-1-(4-(2-oxooxazolidin-3-yl)phenyl)-1H-pyrrol-2-yl)propanoate(see compound 266, Table IV) (105 mg, 0.22 mmol) in THF/H₂O (1 mL,v/v=1/1) was added 2 equivalents of lithium hydroxide monohydrate (19mg, 0.43 mmol). The mixture was stirred at room temperature for 24 h.THF was evaporated in vacuo. The residue was acidified to pH=5 with 5%hydrochloric acid, concentrated and purified by prep-HPLC to afford thetitle compound as a brown solid (68 mg, yield 73%).

Step 1: Synthesis of 4-(2-bromo-1H-pyrrol-1-yl)-3-methylbenzonitrile(50B). To a solution of 3-methyl-4-(1H-pyrrol-1-yl)benzamide (6A, seefirst step of Scheme 6 for synthesis) in DMF (5 mL) was addedN-bromosuccinimide (177 mg, 1 mmol) portionwise at 0° C., after theaddition was completed, the mixture was stirred at room temperature for35 min. The reaction mixture was poured into water, and extracted withethyl acetate (10 mL×3). The combined organic layers were washed withbrine (25 mL×2), dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was purified by columnchromatography on silica gel (petroleum ether/ethyl acetate=5:1) toafford 50B (100 mg, yield 36%).

Step 2: Synthesis of4-(2-bromo-5-formyl-1H-pyrrol-1-yl)-3-methylbenzonitrile (50C). DMF (0.1mL) was added to phosphorus oxychloride (0.5 mL, 5.2 mmol) at 0° C., andthe mixture was stirred at room temperature for 1.5 h. At 0° C., asolution of compound 50B (100 mg. 0.36 mmol) in DMF (2 mL) was added,and the resultant mixture was stirred at room temperature for 30 min.The reaction mixture was poured into ice-water, adjusted to pH=8 withsaturated aqueous sodium carbonate solution, and extracted with ethylacetate (10 mL×3). The combined organic layers were washed with brine(20 mL×2), dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was purified bypreparative TLC to afford 50C (60 mg, yield 58%).

Step 3: Synthesis of4-(2-formyl-5-(4-methoxyphenyl)-1H-pyrrol-1-yl)-3-methylbenzonitrile(50D). A mixture of compound 50C (24 mg, 0.083 mmol), compound4-methoxyphenylboronic acid (15.2 mg, 0.1 mmol) and sodium carbonate(17.6 mg, 0.166 mmol) in a mixture of DME (5 mL) and water (1 mL) wasdegassed, and[11′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (96 mg,0.008 mmol) was added. The reaction mixture was heated at 90° C. for 10hours, poured into water, and extracted with ethyl acetate (10 mL×3).The combine organic layers were washed with brine (20 mL×2), dried overanhydrous sodium sulfate, filtered, and concentrate under reducedpressure, and purified by preparative TLC to afford the compound 50D (15mg, 57%).

Step 4: Synthesis of (E)-ethyl3-(1-(4-cyano-2-methylphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)-2-methylacrylate(50E). A mixture of compound 50D (300 mg, 0.9 mmol) andPh3P═CH(CH3)CO2Et (360 mg, 0.99 mmol) in toluene (10 mL) was heated at120° C. for 10 h. The reaction mixture was concentrated, and the residuewas purified by column chromatography on silica gel (petroleumether/ethyl acetate=15:1) to afford 50E (220 mg, 61% yield), whichcontained some of Ph₃OP and was used in the next step directly.

Step 5: Synthesis of ethyl3-(1-(4-cyano-2-methylphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)-2-methylpropanoate(50F). (E)-ethyl3-(1-(4-cyano-2-methylphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)-2-methylacrylate(50E) was converted to the title compound (50F) following the sameprocedure described in Scheme 6, step 4.

Step 6 and Step 7: Synthesis of3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)-2-methylpropanoicacid (50G). Ethyl3-(1-(4-cyano-2-methylphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)-2-methylpropanoate(50F) was converted to the title compound (50G) following the sameprocedure described in Scheme 6, steps 7 and 8.

The following Methods describe the synthesis of intermediates/startingmaterials used in Schemes described above:

Method 1 Synthesis of 4-Amino-3-chloro-benzamide

A 18 ml vial was loaded with 4-Amino-3-chloro-benzoic acid ethyl ester(350 mg, 1.88 mmole) and 5 ml of 30% NH₄OH. The vial was sealed and themixture was heated at 50° C. for 3 days. The mixture was cooled down andconcentrated to half. The suspension was filtered off, solid was washedwith water and dried to give 200 mg product, 62.3% yield.

Method 2 Synthesis of 1-(6-imidazol-1-yl-pyridin-3-yl)-ethanone

To a 25 mL vial which contained 1-(6-chloro-pyridin-3-yl)-ethanone (1.5g, 10 mmol.) was added 1H-imidazole (3 g, 50 mmol.) at rt. The mixturewas stirred at 120-130° C. for 2 h and cooled to rt. The contents werepoured into 150 mL ice-water solution and extracted with EtOAc (3×100mL). The combined organic layers was washed with water (3×50 mL), brine(50 mL) and dried over Na₂SO₄. The solvent was removed under vacuum toyield the crude which was purified by column to afford desired1-(6-imidazol-1-yl-pyridin-3-yl)-ethanone (1.25 g, 67%).

Method 3 4-(1H-imidazol-2-yl)-2-methylaniline

Step 1: Synthesis of 2-(3-methyl-4-nitrophenyl)-1H-imidazole. To asolution of 3-methyl-4-nitrobenzaldehyde (1.00 g, 6.06 mmol) in THF (6mL) was added conc. NH₃ (4 mL), MeOH (5 mL) and 40% glyoxal (1.32 g,9.09 mmol) at 0° C. The resulting mixture was stirred overnight at roomtemperature and evaporated under reduced pressure. The residue wasrinsed with water (100 mL) and then purified by silica gel columnchromatography (PE:EA=3:1) to afford2-(3-methyl-4-nitrophenyl)-1H-imidazole as a brown solid (295 mg, 24%).

Step 2: Synthesis of 4-(1H-imidazol-2-yl)-2-methylaniline. To a mixtureof 2-(3-methyl-4-nitrophenyl)-1H-imidazole (1.17 g, 5.76 mmol) and 10%Pd/C (0.8 g) in EtOH (5 mL) was added dropwise HCO₂NH_(4 [)3.63 g, 57.64mmol., dissolving in MeOH (50 mL)]. After 1 h, TLC showed the reactionwas complete. Filtration and the filtrate was evaporated under reducedpressure. The residue was dissolved in DCM (30 mL) and filtrated. Thefiltrate was concentrated to afford 4-(1H-imidazol-2-yl)-2-methylanilineas a yellow solid (1.0 g, 99%).

Method 4 2-methyl-4-(oxazol-2-yl)aniline

Step 1: Synthesis of 2-(3-methyl-4-nitrophenyl)oxazole. A mixture of3-methyl-4-nitrobenzaldehyde (500 mg) and diethyl aminoacetal (404 mg,3.03 mmol) was heated at 115° C. for 3 h. After cooling to roomtemperature, conc. H₂SO₄ (4.2 mL) was added by one portion and themixture of P₂O₅ (1.44 g, 10.15 mmol) and H₂SO₄ (0.5 mL) was dropped intowithin 5 min. The resulting mixture was heated at 180° C. for 20 min andthen poured into ice-water (100 mL), which was neutralized with ammonia.A precipitate was filtered and purified by prep-TLC (PE:EA=4:1) toafford 2-(3-methyl-4-nitrophenyl)oxazole as a white solid (91 mg, 14%).

Step 2: Synthesis of 2-methyl-4-(oxazol-2-yl)aniline. Under nitrogenatmosphere, 2-(3-methyl-4-nitrophenyl)oxazole (50 mg, 0.25 mmol),HCOONH₄ (32 mg, 5.90 mmol) and Pd/C (10%, 13 mg) were added intomethanol (5 mL). After having been stirred at 35° C. for 6 h, themixture was filtered, concentrated and purified by prep-TLC (DCM) toafford 2-methyl-4-(oxazol-2-yl)aniline as a yellow solid (24 mg, 56%).

Method 5 5-Amino-2,3-dihydro-isoindol-1-one

Step 1: Synthesis of 2-Methyl-4-nitro-benzoic acid methyl ester. To asolution of 2-methyl-4-nitro-benzoic acid (3 g, 16.56 mmole) in 30 mlmethanol was added at 0° C. sulfuric acid (95-98%, 10 ml) slowly for ½hr. The reaction mixture was stirred at 70° C. for 24 hrs. Mixture wascooled down, a solid precipitated out, then the mixture wasconcentrated, diluted with 50 ml water, stirred for 10 minutes, filteredoff, the solid was washed with water, dried to afford 3.08 g of brownsolid, 95.3% yield, pure by H NMR.

Step 2: Synthesis of 2-bromomethyl-4-nitro-benzoic acid methyl ester. Toa solution of 2-Methyl-4-nitro-benzoic acid methyl ester (3.08 g, 15.79mmole) in 125 ml carbontetrachloride was added NBS (3.1 g, 17.38 mmole)and AIBN (390 mg, 2.38 mmole). The reaction mixture was heated at refluxunder light for 22 hours. The reaction mixture was cooled down,concentrated to half, filtered off, solid was washed with 25 mlcarbontetrachloride. The filtrate was concentrated to give 4 g crudeproduct, containing about 20% unreacted starting material. This was usedfor next step without purification.

Step 3: Synthesis of 5-Nitro-2,3-dihydro-isoindol-1-one. The crude fromthe previous step (4 g) was placed in a 100 ml round bottom flask, thena solution of 7N NH₃ in MeOH was added. The mixture was stirred at roomtemperature, overnight. The mixture was concentrated down to a solidresidue, then triturated with 75 ml ethylacetate. The suspension wasfiltered off, solid was dried to give 1.8 g product, pure by HNMR, 64%over 2 steps yield.

Step 4: Synthesis of 5-Amino-2,3-dihydro-isoindol-1-one. To a suspensionof Fe (1.1 g, 19.6 mmole), NH₄Cl (1.5 g, 28 mmole) in a mixture ofethanol/water (30 ml/7 ml) at 80° C. was added a mixture of5-Nitro-2,3-dihydro-isoindol-1-one (1 g, 5.6 mmole) in 10 ml ethanol.The reaction mixture was stirred at 80° C. for 2 hours. Mixture wascooled down, filtered off, solid was washed with 50 ml ethanol. Thefiltrate was concentrated, taken into 50 ml ethylacetate, washed with 20ml water. Organic layer was dried over Na₂SO₄, filtered and concentratedto give about 900 mg crude. Trituration with methyl t-butylether gave400 mg pure product, 48% yield.

Method 6 5-Amino-pyridine-2-carboxylic acid amide

A 18 ml vial was loaded with a mixture of 30% H₂O₂ (1 ml), 3N NaOH (3ml) and MeOH (2.5 ml). To this mixture 5-Amino-pyridine-2-carbonitrile(450 mg, 3.78 mmole) was added at room temperature. Reaction mixture wasstirred at rt for 45 minutes, TLC showed the starting material to beconsumed. The mixture was diluted with water and filtered; the solid waswashed with water and dried to give 480 mg product, 92% yield.

Method 7 6-Amino-benzothiazol-2-yl)-carbamic acid tert-butyl ester

Step 1: Synthesis of 6-Nitro-benzothiazol-2-yl)-carbamic acid tert-butylester. A 100 ml RBF was loaded with 2-amino-6-nitrobenzothiazole (3 g,15.36 mmole) and 45 ml DMF. To this solution DMAP (936 mg, 7.68 mmole)and BOC anhydride (5 g, 23 mmole) were added. The solution was heated at90° C. for 1 hour. After the mixture was allowed to cool to roomtemperature, a bulky solid formed. The suspension was filtered off,solid was washed with water and dried to give 2.5 g product. Thefiltrate was concentrated to half, diluted with MeOH. More solidprecipitated out. The suspension was filtered off, the solid was washedwith water and dried to give 1 g product, a total of 3.5 g, 87.5% yield.

Step 2: Synthesis of 6-Amino-benzothiazol-2-yl)-carbamic acid tert-butylester. A 250 mL RBF was loaded with 6-nitro-benzothiazol-2-yl)-carbamicacid tert-butyl ester (1.2 g, 4 mmole) and 20 ml THF. To this solutionwas added 10% Pd/C (400 mg, 0.37 mmole). The reaction mixture wasstirred at 30-40 psi for about 2 hours. Mixture was diluted with 50 mlTHF, filtered off trough a celite pad, washed with MeOH. Filtrate wasconcentrated to give 600 mg product, 60% yield.

Method 8 5-Amino-thiophene-2-carboxylic acid amide

A 18 ml vial was loaded with 5-amino-thiophene-2-carboxylic acidmethylester (250 mg, 1.59 mmole) and 5 ml of 30% NH₄OH. The vial wassealed and the mixture was heated at 60° C. for 24 hours. The mixturewas cooled down and concentrated to give 200 mg crude product, 47.4%yield.

Method 9 4-Amino-thiophene-2-carboxylic acid amide

Followed same procedure as described in Method 8.

Method 10 Synthesis of 2-(2-Amino-thiazol-4-yl)-acetamide

A 18 ml vial was loaded with (2-Amino-thiazol-4-yl)-acetic acid ethylester (500 mg, 2.68 mmole) and 5 ml of 30% NH₄OH. The vial was sealedand the mixture was heated at 50° C. for 3 days. The mixture was cooleddown and concentrated to half. The suspension was filtered off, solidwas washed with water and dried to give 200 mg product, 47.4% yield

Method 11 Synthesis of2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine

Synthesis of Compound 11-2. Compound 11-1 (5.0 g, 2.86 mmol) was addedportionwise to POCl₃ (15 mL) at 0° C. during 10 min. The reactionmixture was stirred at 120° C. for 4 h, then cooled to room temperatureand added to ice-water (100 mL). Sat. Na₂CO₃ was added to adjust pH=7and extracted with ethyl acetate (200 mL×4). The combined organic layerswere dried over Na₂SO₄, filtered and concentrated to afford 11-2, whichwas used in the next step without further purification (4.50 g, 80%).

Synthesis of Compound 11-3. To a solution of 11-2 (2.0 g, 10 mmol) inmethanol (15 mL) was added CH₃ONa (2.16 g, 40 mmol). The resultingmixture was stirred at 70° C. overnight. Methanol was evaporated invacuum. Water (10 mL) was added carefully to the residue and the mixturewas extracted with ethyl acetate (300 mL×3). The combined organic layerswere dried over Na₂SO₄, filtered and concentrated to afford 11-3 as ayellow solid (1.17 g, 60%).

Synthesis of Compound 11-4. To a solution of 11-3 (800 mg, 4.26 mmol)and potassium acetate (1.25 g, 12.77 mmol) in solvent(DME/H₂O/Toluene/EtOH=10/1/6/3, 7 mL) was added Pd(dppf)Cl₂DCM (700 mg,0.85 mmol) and Bis(pinacolato)diboron (2.44 g, 9.6 mmol). After havingbeen degassed and recharged with nitrogen, the reaction mixture wasstirred at 85° C. overnight. TLC showed the reaction was complete. Aftercooling to room temperature, water (10 mL) was added and extracted withethyl acetate (30 mL×3). The combined organic layers were dried overNa₂SO₄, filtered, concentrated and purified by silica gel columnchromatography (PE:EA=5:1) to afford 11-4 as a yellow solid (1.0 g,98%).

Method 12 Synthesis of2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

Compound 12-2. A solution of 12-1 (12.3 g, 0.06 mmol),Bis(pinacolato)diboron (18.3 g, 0.072 mol), KOAc (11.75 g, 0.12 mmol)and Pd(dppf)₂Cl₂DCM (2.0 g, 2.45 mmol) in dioxane/H₂O (v/v=9/1, 100 mL)was stirred at 80° C. overnight. TLC showed that the reaction wascomplete. The mixture was evaporated to afford a brown oil. Water (60mL) was added and the mixture was extracted with ethyl acetate (60mL×3). The combined organic layers were dried over MgSO₄, filtered,concentrated and purified by silica gel column chromatography(PE:EA=10:1) to afford 12-2 as a yellow solid (9.1 g, 60%).

Method 13 Synthesis of 2-methyl-4-(thiazol-2-yl)aniline

Compound 13-2. To a mixture of 4-bromo-2-methylbenzenamine (500 mg, 2.69mmol), KOAc (1.32 g, 13.4 mmol) and bis(pinacolato)diboron (2.05 mg, 8.0mmol) in dioxane (4 mL) was added Pd(dppf)Cl₂ (110 mg, 0.134 mmol).After having been degassed and recharged with nitrogen, the mixture wasrefluxed at 85° C. for 16 h. TLC showed that the reaction was complete.Water (20 mL) was added and the mixture was extracted with ethyl acetate(30 mL×3). The combined organic layers were dried over Na₂SO₄, filtered,concentrated and purified by silica gel column chromatography (DCM) toafford 13-2 as a white solid (485 mg, yield 77%).

Compound 13-3. To a mixture of 13-2 (257 mg, 1.57 mmol), K₂CO₃ (653 mg,4.7 mmol) and 2-bromothiazole (367 mg, 1.57 mmol) in the mixed solvent(Dioxane/H₂O=2/1, 15 mL) was added Pd(PPh₃)₄ (182 mg, 0.157 mmol). Afterhaving been degassed and recharged with nitrogen, the mixture wasrefluxed at 85° C. for 11 h. TLC showed that the reaction was complete.Water (10 mL) was added and the mixture was extracted with ethyl acetate(20 mL×3). The combined organic layers were dried over Na₂SO₄, filtered,concentrated and purified by silica gel column chromatography(PE:Acetone=10:1) to afford 13-3 as a yellow oil (229 mg, yield 76%).

Method 14 Synthesis of 2-cyclopropyl-1H-imidazole

Compound 14-1. To a solution of cyclopropane carbonitrile (2.68 g, 40mmol) in 30 mL of HCl (4 N in dioxane) was added dry ethanol (1.84 g, 40mmol) and stirred at room temperature overnight. Then PE (50 mL) wasadded and the mixture was filtered. The filter cake was washed with PE(50 mL) and dried in vacuo to give a white solid (5.98 g, yield 100%).

Compound 14-2. To a mixture of 14-1 (2.50 g, 16.7 mmol, 1.0 eq) in CH₃CN(50 mL) was added ethane-1,2-diamine (1.2 g, 20.1 mmol, 1.2 eq). Themixture was heated under reflux for 0.5 h and cooled to roomtemperature. The reaction mixture was concentrated in vacuo to afford14-2 (2.17 g) as a white solid, which was used for next step withoutpurification.

Compound 14-3. To a mixture of 14-2 (2.17 g, 16.7 mmol, 1.0 eq) in CH₃CN(50 mL) was added KMnO₄ (1.58 g, 66.8 mmol, 4.0 eq) and silica gel (10.0g, 200-300 mesh). The reaction mixture was stirred at room temperatureovernight and methanol (about 5 mL) was added to the solution. Themixture was filtered and concentrated in vacuo to afford 14-3 as a whitesolid. (1.15 g, two steps yield 64%).

Method 15 Synthesis of 1-(4-bromo-2-methoxyphenyl)ethanone

Compound 15-1. To a stirred suspension of 3-bromophenol (50 g, 0.29 mol)in pyridine (200 mL) and dichloromethane (100 mL) was added dropwiseacetyl chloride (25 mL, 0.35 mol) at 0° C. and the mixture was stirred18 h at room temperature. LC-MS showed that the reaction was complete.Pyridine and dichloromethane was evaporated in vacuo. Water (600 mL) wasadded and acidified with hydrochloric acid at pH 2. The reaction mixturewas extracted with ethyl acetate (500 mL×3) and the organic phase wasdried over anhydrous sodium sulfate, filtrated, concentrated andpurified by column chromatography (PE:EA=60:1) to afford compound 15-1as a colorless liquid (46 g, 74%).

Compound 15-2. To a stirred suspensions of compound 15-1 (46 g, 0.0.21mol) and anhydrous aluminum chloride power (57 g, 0.42 mol) was heatedto 160° C. for 3 h. The mixture reaction was cooled to room temperatureand ice (200 g) and water (800 mL) was poured and purified withhydrochloric acid at pH 7. the reaction was extracted with ethyl acetate(500 mL×3) and the organic phase was washed with saturated sodiumbicarbonate, dried over anhydrous sodium sulfate, filtrated,concentrated and purified by column chromatography (PE:EA=60:1) toafford compound 15-2 as a light green solid (35.1 g, 76%).

Compound 15-3. To a suspensions of compound 15-2 (25 g, 0.12 mol) andpotassium carbonate (24 g, 0.18 mol) in anhydrous DMF (20 mL) was addedto MeI (22.6 mL, 0.23 mol) and the mixture reaction was stirred at roomtemperature overnight. LCMS showed that the reaction was complete. Thenwater (300 mL) was poured and the mixture was extracted with ethylacetate and the organic phase was (200 mL×3) and the organic phase waswashed saturated sodium chloride, dried over anhydrous sodium sulfate,filtrated, concentrated to afford compound 15-3 as a colorless solid(26.1 g, 98%).

Method 16 Synthesis of ethyl3-(5-(2-amino-4-chlorophenyl)-1-(4-cyano-2-methylphenyl)-1H-pyrrol-2-yl)propanoate

Compound 16-2. To a solution of 16-1 (6.50 g, 27.66 mmol) and NiCl₂(7.80 g, 55.3 mmol) in EtOH (50 mL) was added NaBH₄ (5.60 g, 138.3 mmol)slowly. The resultant mixture was stirred at 0° C. for 2 h, filtered andconcentrated under reduced pressure. The residue was dissolved withethyl acetate (200 mL), washed with water (50 mL×3), dried over Na₂SO₄,concentrated and purified by silica gel column (PE:EA=5:1) to afford16-2 as a dark solid (3.778 g, yield 67%).

Compound 16-3. A solution of 16-2 (3.778 g, 18.43 mmol),Bis(pinacolato)diboron (8.5 g, 33.17 mol), KOAc (3.2 g, 36.86 mmol) andPd(dppf)₂Cl₂DCM (500 mg, 0.92 mmol) in DMSO (50 mL) was stirred at 85°C. for 2.5 h. TLC showed that the reaction was complete. Water (60 mL)was added and the mixture was extracted with ethyl acetate (60 mL×3).The combined organic layers were dried over Na₂SO₄, filtered,concentrated and purified by silica gel column (PE:EA=10:1) to afford16-3 as a yellow solid (5.0 g, yield 100%).

Compound 16-4. To a solution of 16-3 (7.0 g, 27.7 mmol), Na₂CO₃ (11.75g, 110.8 mmol) and 6E (ethyl3-(5-bromo-1-(4-cyano-2-methylphenyl)-1H-pyrrol-2-yl)propanoate, seeScheme 6 for synthesis) (10 g, 21.4 mmol) in DMSO (30 mL) was addedPd(PPh₃)₄ (3.0 g, 8.31 mmol). After having been degassed and rechargedwith nitrogen, the reaction mixture was stirred at 80° C. overnight. TLCshowed the reaction was complete. After cooling to room temperature,water (50 mL) was added and extracted with ethyl acetate (50 mL×4). Thecombined organic layers were dried over Na₂SO₄, filtered, concentratedand purified by silica gel column chromatography (PE:EA=3:1) to afford16-4 as a yellow solid (3.10 g, yield 27%).

Method 17 Synthesis of 4-chloro-2-(methoxymethyl)phenylboronic acid

Compound 17-2. Compound 17-1 (5.0 g, 21.23 mmol) was added to BH₃/THF (1M, 85 mL) under nitrogen atmosphere at 10° C. After addition, themixture was stirred at room temperature overnight, quenched withmethanol (30 mL) at 0° C. and concentrated to dryness. The residue wasdissolved in methanol (100 mL) and concentrated to dryness again. Thisoperation was repeated twice to afford 17-2 as a white solid (4.7 g,quantitative yield).

Compound 17-3. To a solution of compound 17-2 (8.0 g, 36.1 mmol) in THF(60 mL) was added NaH (60%, 1.88 g, 46.9 mmol) at 0° C. After addition,the reaction mixture was stirred at room temperature for 30 min.Iodomethane (10.25 g, 72.2 mmol) was added and stirred for another 30min. The reaction was then quenched with sat. ammonium chloride (50 mL)and extracted with ethyl acetate (50 mL×3). The combined organic layerswere washed with brine (60 mL), dried over Na₂SO₄, filtered,concentrated to afford 17-3 as a white solid (7.23 g, yield 85%).

Compound 17-4. To a mixture of 17-3 (3 g, 12.8 mmol) and triisopropylborate (3.5 mL, 15.4 mmol) in THF (30 mL) at −76° C. was added n-BuLi(2.5 M in hexanes, 5.1 mL, 12.8 mmol) at a rate keeping the temperaturebelow −69° C. The reaction was aged 20 min, allowed to warm to −20° C.and quenched with 2 M hydrochloric acid until the pH=4. The mixture wasextracted with ethyl acetate (50 mL×3). The combined organic layers weredried over Na₂SO₄, filtered, concentrated to afford 17-4 as a pale whitesolid (1.2 g, 47%).

Method 18 Synthesis of3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol

Compound 18-2. Prepared following the same procedure described in thefirst step of Method 13, with column purification using a differentsolvent system of (PE:EA=5:1) to give 35% yield of desired.

Method 19 Synthesis of 1-(5-bromothiophen-3-yl)ethanone

Compound 19-2. To a solution of 3-acetylthiophene (2.52 g, 20 mmol, 1.0eq) in HOAc (50 mL) was added NaOAc (2.46 g, 30 mmol, 1.5 eq) followedby bromine (3.2 g, 20 mmol, 1.0 eq) dropwise over 30 min. The mixturewas allowed to stir at rt overnight. Water (150 mL) was added and thereaction mixture was stirred for 2 h. The resulting solid was collectedby filtration, rinsed with water (10 mL) and PE (20 mL) and dried toafford 19-2 as a brown solid (1.52 g, yield 37%).

Method 20 Synthesis of N-(4-amino-3-methylphenyl)acetamide

Compound 20-2: To an ice-cold solution of 20-1 (40 g, 222 mmol) in 400mL of MeOH/H₂O (v/v=1/1) was added NaOH (35.6 g, 888 mmol), stirred for0.5 h, and NaClO (380 g, 556 mmol) was added drop wise at 0° C. Themixture was warmed to room temperature (20° C.)., stirred for 18 h. Thenthe mixture was warmed to 35° C. stirred for 1 h, warmed to 75° C.stirred for 0.5 h. The mixture was cooled to room temperature, con. HClwas added to adjust pH=6.0 with brown precipitate appeared, filtratedand washed with water (200 mL×2) to afford 20-2 (29 g, 86%) as a tanpowder.

Compound 20-3: To a solution of Pyridine (20 mL) and AcCl (6.158 g,78.947) in DCM (100 mL) was added the solution of 20-2 (10 g, 65.789mmol) in pyridine (20 mL) at 0° C. The mixture was stirred at roomtemperature for 3 h. The volatiles were removed under reduced pressureand the residue was washed with water (100 mL×3), dried under reducedpressure to afford 20-3 as yellow solid (12.5 g, yield: 97%).

Compound 20-4: To the solution of 20-3 (12 g, 61.86 mmol) in MeOH (200mL) was added 10% Pd/C (1.5 g) purged with N₂. Then the solution ofHCO₂NH₄ (39 g, 618.56 mmol) in MeOH (300 mL) was added gradually to theice-cooled solution obtained. The mixture was warmed to 45° C., stirredat this temperature overnight. After filtrated, the filtrate wasevaporated under reduced pressure. The residue was extracted with EA(200 mL×3), the organic layers were evaporated under reduced pressure,purified by silica gel column chromatography (PE:EA=1:2) to afford 20-4as brown oil (3.1 g, yield: 30%).

Method 21 Synthesis of 1-(4-chloro-2-methoxyphenyl)ethanone

Synthesis of 21-4: Followed methods analogous to the three stepsdescribed in Method 15.

Method 22 Synthesis of 1-(4-bromothiazol-2-yl)ethanone

Compound 22-2. A mixture of 22-1 (5.0 g, 38.42 mmol) and POBr₃ (55.07 g,192.09 mmol) was stirred at 110° C. for 3 h, then cooled to 55° C. andpoured onto ice (300 g). Solid Na₂CO₃ (40 g) was added portionwise andthe mixture was extracted with EA (150 mL×3). The combined organiclayers were washed with brine (80 mL), dried over Na₂SO₄, filtered,concentrated and purified by silica gel column chromatography (pure PEto PE:EA=50:1) to afford 22-2 as a white solid (4.86 g, yield 47%).

Compound 22-3. To a solution of compound 22-2 (3.0 g, 12.35 mmol) in THF(25 mL) was added dropwise n-BuLi (2.5 M in hexane, 2.5 mL) at −78° C.After addition, the reaction mixture was stirred at −78° C. for 30 min.N-acetyl morpholine (1.9 mL, 16.06 mmol) was added dropwise during 15min at −78° C. After addition, the reaction mixture was stirred at −78°C. for 4 h, then quenched with sat. NaHCO₃ (15 mL) and extracted withethyl acetate (25 mL×4). The combined organic layers were washed withbrine (30 mL), dried over Na₂SO₄, filtered, concentrated and purified bysilica gel column chromatography (PE:EA=50:1 to 10:1) to afford 22-3-3as a white solid (1.28 g, yield 50%).

Method 23 Synthesis of N-(4-aminophenyl)methanesulfonamide (23-3, R=H)and N-(4-amino-3-methylphenyl)methanesulfonamide (23-3, R=CH₃)

Representative Example for Method 23 Synthesis ofN-(4-aminophenyl)methanesulfonamide (23-3, R=H)

Compound 23-2, R=H. To a solution of pyridine (50 mL) and MsCl (15.86 g,139.13 mmol) in DCM (150 mL) was added the solution of4-nitrobenzenamine (16.0 g, 115.94 mmol) in pyridine (100 mL) at 0° C.The mixture was stirred at room temperature for 4 h. The volatiles wereremoved under reduced pressure. The residue was rinsed with water (200mL×3) and dried under reduced pressure to afford the title compound as ayellow powder (23.20 g, yield 95%).

Compound 23-3, R=H. To a solution of 23-2, R=H (23.0 g, 106.48 mmol) inMeOH (100 mL) was added 10% Pd/C (3.0 g) purged with N₂. Then a solutionof HCO₂NH₄ (67.0 g, 1.06 mol) in MeOH (500 mL) was added gradually underice-water bath during 5 min. After addition, the mixture was warmed to45° C. and stirred overnight and filtered. The filtrate was evaporatedunder reduced pressure to afford yellow solid which was washed with EA(500 mL×3). The combined organic layers were evaporated under reducedpressure, purified by silica gel column chromatography (PE:EA=1:2) toafford N-(4-aminophenyl)methanesulfonamide as a yellow solid (9.80 g,yield 49%).

Method 24 Synthesis of 1-(3-chlorothiophen-2-yl)ethanone

Compound 24-1. To a solution of 3-chlorothiophene (4.80 g, 40.48 mmol)in THF (50 mL) was added BuLi (2.5N in hexane, 17.9 mL) at −30° C. Afteraddition, the mixture was stirred for 30 min at −10° C., and then cooledto −45° C. N-methoxy-N-methyl acetamide (55.0 g, 48.8 mmol) was addedand allowed to warm to room temperature during 40 min and maintained foran additional 20 min. Brine (80 mL) was added to quench the reaction,extracted with EA (60 mL×3). The combined organic layers were dried overanhydrous Na₂SO₄, filtered, concentrated to afford 24-1 (−80% pure) as ayellow oil (6.80 g) which used for the next step directly.

Method 25 Synthesis of 1-(3-bromo-5-methoxythiophen-2-yl)ethanone

Compound 25-1. To a suspension of N,O-dimethylhydroamine hydrochloride(100 g, 1026 mmol) in DCM (1000 mL) was added triethylamine (300 mL,2052 mmol) at 0° C. Acetyl chloride was added dropwise to the suspensionfor 2 h at 0° C. When the addition was complete, the mixture was allowedto warm to rt and stirred for 2 h. The mixture was washed with brine (1L), 1 N HCl (500 mL), brine (200 mL) respectively and dried withmagnesium sulfate, filtered and concentrated to afford brown oil, whichwas purified by distillation to afford 25-1 as a colourless liquid (65g, 61%).

Compound 25-2. To a solution of thiophene (84 g, 1.0 mol) in chloroform(34 mL) was added dropwise bromine at rt for 3 h. When the addition wascomplete, the mixture was stirred at rt overnight. The mixture washeated to 50° C. for 3 h. The reaction mixture was washed with 1M NaOH(aq. 100 mL), brine (100 mL×2) respectively. The organic phase was driedwith anhydrous sodium sulfate, filtered and concentrated to afford lightyellow oil, which was solidified in methanol (100 mL). The solid wasfiltered and dried in vacuo to afford 25-2 (89 g, 56%).

Compound 25-3. 25-2 (9.5 g, 30 mmol) was dissolved in anhydrous THF (100mL) and cooled to −78° C. To the above solution was added dropwisen-BuLi (8 mL, 21 mmol) for 30 min and stirred for 30 min. 25-1 was addeddropwise at −78° C., stirred for 30 min and allowed to warm to rt beforequenching with saturated ammonium chloride. The organic phase wasseparated and washed with brine, dried with anhydrous Na₂SO₄, filteredand concentrated to afford yellow oil, which was purified by columnchromatography (elution: PE/EA=10/1) afford 25-3 as a yellow solid (2.3g, 28%).

Compound 25-4. To a solution of 25-3 (2.4 g, 8.5 mmol) in methanol (35mL) was added trimethyl orthoformate (15 mL) and TsOH (300 mg, 1.7mmol). The solution was heated to reflux for 10 h. Methanol wasevaporated in vacuo and the residue was partitioned between EA (300 mL)and 5% sodium bicarbonate (100 mL). The organic phase was separated,dried with anhydrous sodium sulfate, filtered and concentrated to afford25-4 as a yellow oil, which was used directly for next step (2.3 g,82%).

Compound 25-5. To a solution of 25-4 (6.0 g, 18.3 mmol) in DMF (75 mL)was added sodium methoxide (9.9 g, 183 mmol), cuprous oxide (1.5 g, 18.3mmol) and sodium iodide (2.8 g, 18.3 mmol). The mixture was heated to100° C. for 4 h. TLC indicated that the reaction was complete and thereaction was quenched with brine (250 mL). The solid was filtered andthe filtrate was extracted with ethyl acetate (100 mL×3). The combinedorganic layers were dried with anhydrous sodium sulfate, filtered andconcentrated to afford brown oil, which was purified by columnchromatography (elution: PE/EA=3/1) to afford 25-5 as a light yellow oil(1.2 g, 23%).

Compound 25-6. To a solution of 25-5 (1.2 g, 4.29 mmol) in DCM (8 mL)and water (10 mL) was added trifluoroacetic acid (10 mL). The reactionmixture was stirred at rt for 4 h. Saturated sodium bicarbonate (10 mL)was added and the organic phase was separated, dried with anhydroussodium sulfate, filtered and concentrated to afford brown oil, which waspurified by column chromatography (elution: PE/EA=10/1) to afford 25-6as a light yellow solid (750 g, 74%).

Method 26 Synthesis of (1H-imidazol-2-yl)methanol

Compound 26-2. To a solution of 2-imidazolecarboxyaldehyde (26-1) (1.92g, 20 mmol, 1.0 eq) was suspended in methanol (30 mL), NaBH₄ (1.52 g, 40mmol, 2.0 eq) was added portion-wise. The reaction mixture was stirredat room temperature for 1 h under N₂. It was quenched with 5 mL ofbrine. The solvent was removed and the solid was purified with silicagel column chromatography (DCM:MeOH=20:1) to afford a white solid. (1.0g, Yield: 51%).

Method 27 Synthesis of 4-amino-3-methylbenzenesulfonamide

Compound 27-2: Ac₂O (16 ml, 0.16 mol) was added to the solution of 27-1(20 g, 0.107 mol) in 80 ml of pyridine. The mixture was stirred at rtfor 2 hours. Then EtOH (40 ml) was added and the solid was isolated byfiltration and washed with EtOH to give 27-2 as a brown solid (10.3 g,yield 56%).

Compound 27-3: Compound 27-2 (10 g, 43.6 mmol) was added to a flaskcontaining 1 N NaOH (36 ml) and the mixture was stirred at rt for 3hours. The solvent was removed and the residue was washed with EtOH.27-3 was isolated by filtration as a pale solid (8.8 g, yield 88%).

Compound 27-4: Compound 27-3 (16 g, 63.7 mmol) and DMF (20 ml) wereadded to a flask and then SOCl₂ (18.4 g, 155 mol) was added dropwise at−30-40° C. When the addition was complete, the mixture was stirred at rtfor 2 hours. Then the mixture was added to ice slowly and solidappeared. The solid was isolated by filtration and dried to give 27-4 asa pale solid (6.0 g, yield 38%).

Compound 27-5: The solution of 27-4 (6.0 g, 24.2 mmol) in 50 ml of THFwas added to 50 ml of NH₄OH at 0° C. dropwise. The mixture was stirredat rt for 1 h. The solvent was removed under reduced pressure and theresidue was extracted with EA (30 ml×4). The organic layer was driedover Na₂SO₄ and filtered, concentrated to give 27-5 as a pale solid (5.1g, yield 93%).

Compound 27-6: A mixture of 27-5 (5.1 g, 22.3 mmol), HCl (2 N, 76.5 ml)and EtOH (100 ml) was refluxed overnight. Then the mixture wasneutralized with Na₂CO₃(aq) to PH=8. The mixture was extracted with EA(80 ml X₄), dried over Na₂SO₄, and concentrated to give 27-6 as a palesolid (4.9 g, yield 100%).

Method 28 Synthesis of 1-(5-bromo-4-chlorothiophen-2-yl)ethanone (28-2)and 1-(4-chlorothiophen-2-yl)ethanone (28-3)

Compound 28-1. To a solution of 3-chlorothiophene (6.52 g, 55 mmol) inCHCl₃ (30 mL) and AcOH (30 mL) was added NBS (9.80 g, 55 mmol). Themixture was heated at relux for 1.5 h, then cooled to room temperature.Water (70 mL) was added and the mixture was extracted with CHCl₃ (30mL×2). The combined organic layers were washed with sat. NaHCO₃ (40 mL)and brine (30 mL), dried over anhydrous Na₂SO₄, filtered, concentratedto afford 28-1 as a brown oil (10.02 g, quantitative yield) which usedfor the next step directly.

Synthesis of 1-(5-bromo-4-chlorothiophen-2-yl)ethanone (28-2). To amixture of 28-1 (10.0 g, 50.6 mmol) and AlCl₃ (8.09 g, 60.7 mmol) in DCM(120 mL) was added dropwise acetyl chloride (4.76 g, 60.7 mmol) during 5min at 0° C. After addition, the mixture was stirred overnight at roomtemperature, washed with diluted hydrochloride acid (1.2N, 150 mL) andbrine (150 mL), dried over anhydrous Na₂SO₄, filtered, concentrated andpurified by silica gel column chromatography (PE/EA=20/1 to 3/1) toafford 28-2 as a brown solid (8.0 mg, yield: 66%).

Synthesis of 1-(4-chlorothiophen-2-yl)ethanone (28-3). To a solution of28-2 (3.20 mg, 13.36 mmol) in EtOH (70 mL) was added 10% Pd/C (2.50 g)and AcONa (1.10 g, 13.36 mmol). The reaction mixture was stirred under ahydrogen atmosphere at room temperature for 3 h, filtered, and thefiltrate was concentrated. The resultant residue was dissolved in EA(100 mL) washed with sat. NaHCO₃ (40 mL) and brine (30 mL), dried overanhydrous Na₂SO₄, filtered, concentrated and purified by silica gelcolumn chromatography (PE/EA=30/1 to 5/1) to afford 28-3 as a yellow oil(1.32 g, yield: 62%).

Method 29 Synthesis of 1-amino-(2-methyl-4-(sulfamoylamino)phenyl)

Compound 29-1. To a solution of 3-methyl-4-nitroaniline (4.50 g, 29.6mmol) in dioxane (90 mL) was added sulfuric diamide (14.2 g, 428 mmol).The reaction mixture was heated to reflux for 119 h. After the removalof the volatile, the residual was dissolved in ethyl acetate (400 mL),and then washed with water (200 mL) and brine (200 mL), dried overNa₂SO₄, filtered, concentrated and purified by silica gel columnchromatography (EA:PE=1:4) to afford 29-1 as a yellow solid (1.84 mg,yield: 27%).

Compound 29-2. To a suspend solution of Pd/C (10%, 200 mg) in methanol(20 mL) was added 29-1 (1.84 g, 7.95 mmol). After having been degassedand recharged with hydrogen gas, the mixture was stirred at roomtemperature for 15 h. TLC showed that the reaction was complete. ThePd/C solid was removed by filtration and then the solvent wasevaporated. The obtained brown solid (550 mg, quant.) was used withoutfurther purification for the next step preparation.

Method 30 Synthesis of 5-methyl-1H-benzo[d]imidazol-6-amine (30-3A) and5-methyl-1H-benzo[d]imidazol-4-amine (30-3B)

Compound 30-2A and 30-2B. 5-Methylbenzimidazole (6.0 g, 45.40 mmol) wasdissolved in concentrated H₂SO₄ (97.5 mL) and cooled to 0° C. Potassiumnitrate (4.135 g, 40.90 mmol) was added portionwise. After stirring for1 h, the reaction mixture was poured over ice and Na₂CO₃ was added toadjust pH >8. The aqueous layer was extracted with EtOAc. The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated invacuo. The resulting yellow solid was recrystallized from 50% MeOH/water(80 mL) to afford a mixture of 30-2A and 30-2B as a brown powder (5.5 g,68%).

Compound 30-3A and 30-3B. To a mixture of 30-2A and 30-2B (5.5 g, 31.073mmol) and 10% Pd/C (1.0 g) in EtOH (5 mL) was added dropwise thesolution of HCO₂NH₄ (19.576 g, 310.73 mmol) in MeOH (200 mL). After 1 h,TLC showed the reaction was complete. Filtration and the filtrate wasevaporated under reduced pressure. The residue was dissolved in DCM (100mL) and filtrated. The filtrate was concentrated and purified by silicagel column chromatography (DCM:MeOH=10:1) to afford 30-3A (2.0 g, 44%)and 30-3B (1.8 g, 39%) as brown solids.

Method 31 Synthesis of isoquinolin-7-amine

Synthesis of 7-nitro-1,2,3,4-tetrahydroisoquinoline (31-2).1,2,3,4-Tetrahydroisoquinoline (4.0 g, 30.0 mmol) was dissolved in 10 Nof sulfuric acid (6 mL, 30.0 mmol) and then evaporated to dryness toafford a solid residual. This sulfate was added slowly to a solution ofpotassium nitrate (3.34 g, 33.0 mmol) in sulfuric acid (15 mL), takingcare that the temperature of the reaction mixture did not rise above 5°C. After being stirred at room temperature for a further 27 h, thereaction mixture was slowly poured into a con. ammonium solution (ca.100 mL) under ice cooling. The resulted solution was extracted withdichloromethane (100 mL×3). The combined organic phase was washed withbrine (150 mL), dried over Na₂SO₄, filtered, concentrated and purifiedby silica gel column chromatography (DCM:MeOH=100:1) to afford 31-2 as abrown solid (2.24 g, yield 41%).

Synthesis of 7-nitroisoquinoline (31-3). Under refluxing, a solution ofiodine (4.0 g, 15.9 mmol) in ethanol (56 mL) was added dropwise to astirred solution of 31-2 (2.0 g, 9.34 mmol) in ethanol (24 mL) during 5h. Then the resulted mixture was stirred for a further 66 h. The solventwas removed and the residual was loaded onto a silica gel chromatographycolumn (PE:EA=6:1) to give 31-3 as a brown dark solid (602 mg, yield36%).

Synthesis of isoquinolin-7-amine (31-4). To a suspend solution of Pd/C(10%, 100 mg) in methanol (20 mL) was added 31-3 (200 mg, 1.15 mmol) inmethanol (40 mL). After having been degassed and recharged withhydrogen, the mixture was then stirred at room temperature for 24.5 h.TLC showed that the reaction was complete. The Pd/C was removed byfiltration and the solvent was evaporated. The residual was used withoutfurther purification (150 mg, yield 90%).

Method 32 Synthesis of isoquinolin-6-amine

Followed same procedure described in the synthesis ofisoquinolin-7-amine, Method 31.

Method 33 Synthesis ofN-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)formamide

Compound 33-2: A mixture of HCO₂H (644 mg, 14 mmol) and Ac₂O (1.16 g,11.4 mmol) was heated to 55° C. for 2 h and then cooled to roomtemperature. THF (1 mL) and 33-1 (880 mg, 4.38 mmol) in THF (1 mL) wasadded stepwise and the resultant mixture was continually stirred at roomtemperature for 3 h. After evaporation, the residue was extracted withEA (5 mL×3). The organic phase was successively washed with sat. aqueoussodium bicarbonate (10 mL) and sodium chloride (10 mL), dried overanhydrous sodium sulfate, filtrated and concentrated to afford 33-2 as aliquid (845 mg, yield: 85%), which was used directly for the next step.

Compound 33-3: To a mixture of 33-2 (845 mg, 4.38 mmol), KOAc (726 mg,7.4 mmol), B(pin)₂ (1.41 g, 5.6 mmol) and dioxane was added Pd(dppf)₂Cl₂(20 mg, 0.02 mmol). After having been degassed and recharged withnitrogen, the mixture was refluxed at 90° C. overnight. TLC showed thatthe reaction was complete. Water (10 mL) was added and the mixture wasextracted with ethyl acetate (10 mL×3). The combined organic layers weredried over Na₂SO₄, filtered, concentrated and purified by silica gelcolumn chromatography (PE:EA=4:1) to afford 33-3 as a colorless solid(220 mg, yield: 29%).

Method 34 Synthesis of 4-(pyridin-3-yloxy)aniline (34-2)

Synthesis of compound 34-1: To a solution of 4-fluorobenzenamine (6.746g, 47.85 mmol) and pyridine-3-ol (5.0 g, 52.63 mmol) in 100 mL of DMFwas added K₂CO₃ (13.21 g, 95.69 mmol). The mixture was heated to 100° C.overnight. Then it was dissolved in 500 mL of EA and washed with water(400 mL×2). The organic layer was concentrated under reduced pressure,the residue was purified by silica gel column (PE/EA=1/5) to afford 34-1(7.8 g, 76%) as brown solid.

Synthesis of compound 34-2: To the solution of 34-1 (2.0 g, 9.259 mmol)in MeOH (20 mL) was added 10% Pd/C (0.2 g) purged with N₂. Then H₂ wasadded to remove N₂. The mixture was stirred at room temperatureovernight. After filtrated, the filtrate was concentrated to drynessaffording 34-2 (1.7 g, 99%) as brown solid.

Method 35 Synthesis of 4-amino-benzenesulfonamide

Followed procedure/scheme described in method 27, Synthesis of4-amino-3-methylbenzenesulfonamide.

Method 36 Synthesis of N-(4-aminophenyl)acetamide

Step 1: Synthesis of N-(4-nitrophenyl)acetamide. To a solution ofPyridine (3 mL) and AcCl (1.017 g, 13.043) in DCM (15 mL) was added thesolution of 4-nitrobenzenamine (1.5 g, 10.870 mmol) in pyridine (3 mL)at 0° C. The mixture was stirred at room temperature for 1 h. Thevolatiles were removed under reduced pressure and the residue was washedwith water (10 mL×3), dried under reduced pressure to affordN-(4-nitrophenyl)acetamide as yellow powder (1.9 g, yield: 97%).

Step 2: Synthesis of N-(4-aminophenyl)acetamide. To the solution ofN-(4-nitrophenyl)acetamide (1.9 g, 10.556 mmol) in MeOH (10 mL) wasadded 10% Pd/C (0.2 g) purged with N₂. Then the solution of HCO₂NH₄ (6.7g, 106 mmol) in MeOH (20 mL) was added gradually to the ice-cooledsolution obtained. The mixture was warmed to 45° C., stirred at thistemperature overnight. After filtrated, the filtrate was removed invacuo. The residue was extracted with EA (30 mL×3), the organic layerwere evaporated under reduced pressure, purified by silica gel columnchromatography (PE:EA=1:2) to afford N-(4-aminophenyl)acetal as a yellowpowder (1.3 g, yield: 82%).

Method 37 Synthesis of 4-(1-methylpyrrolidin-3-yloxy)aniline

Step 1: Synthesis of 1-methyl-3-(4-nitrophenoxy)pyrrolidine. To asolution of potassium tert-butoxide (1.43 g, 12.9 mmol) in THF (6 mL)was added 1-methylpyrrolidin-3-ol (645 mg, 6.39 mmol). The reactionmixture was stirred at room temperature for 1 h. Then1-fluoro-4-nitrobenzene (900 mg, 6.39 mmol) was added to the abovesolution and stirred for another 2 h. After the removal of the volatile,the residual was dissolved in ethyl acetate (40 mL), and then washedwith water (20 mL) and brine (20 mL), dried over Na₂SO₄, filtered,concentrated and purified by silica gel column chromatography(EA:PE=1:4) to give desired product as a yellow oil (626 mg, 44%).

Step 2: Synthesis of 4-(1-methylpyrrolidin-3-yloxy)aniline. Followedsame procedure described in final step of Method 34.

Method 38 Synthesis of 3-(4-aminophenyl)oxazolidin-2-one

Step 1: Synthesis of 3-(4-nitrophenyl)oxazolidin-2-one (38-1). To amixture of 1-bromo-4-nitrobenzene (5.00 g, 25 mmol) and oxazolidin-2-one(3.23 g, 37 mmol) in dioxane (25 mL) were added L-proline (285 mg, 2.5mmol), CuI (238 mg, 1.2 mmol) and K₂CO₃ (6.90 g, 50 mmol). The resultantmixture was stirred under N₂ at 110° C. for 63 h and then evaporated.The residue was diluted with EA/water (40 mL/40 mL). The mixture wasfiltered and the resultant aqueous layer was extracted with EA (30mL×5). The combined organic layers were washed with brine, dried overNaSO₄, concentrated and purified by silica gel column chromatography(DCM to DCM:MeOH=50:1) to afford desired as a yellow solid (1.40 g,yield 27%).

Step 2: Synthesis of 3-(4-aminophenyl)oxazolidin-2-one (38-2). To asolution of 3-(4-nitrophenyl)oxazolidin-2-one (800 mg, 3.8 mmol) in MeOH(10 mL) was added Pd/C (10%, 200 mg). After having been degassed andrecharged with hydrogen from a balloon, the mixture was stirred at rtfor 15 h. TLC showed no starting material existed. The solid Pd/C wasseparated by filtration and the crude product3-(4-aminophenyl)oxazolidin-2-one was obtained by evaporation as ayellow solid (622 mg, yield 90%) and used directly for the next step.

Method 39 Synthesis of 5-aminobenzo[d]oxazol-2(3H)-one (39-2)

Synthesis of 5-nitrobenzo[d]oxazol-2(3H)-one (39-1). The mixture of2-amino-4-nitrophenol (5 g, 32.44 mmol) and CDI (6.3 g, 38.93 mmol) inTHF (60 mL) was heated at refluxing for 16 h. Cooled to roomtemperature, the solvent was removed under reduced pressure, the residuewas dissolved in DCM (100 mL) and poured into 2N HCl solution (200 mL)with stirring, after 30 min, collected the solid and washed with water(50 mL×2), dried in vacuo to get compound 39-1 as a yellow solid (5.1 g,yield 87%).

Synthesis of 5-aminobenzo[d]oxazol-2(3H)-one (39-2). The mixture of 39-1(5.1 g, 28.31 mmol), Pd/C (0.5 g) and HCO₂NH₄ (8.9 g, 141.57 mmol) inMeOH (200 mL) was stirred at room temperature overnight. Filtered withkiselguhr, concentrated in vacuo, the residue was added 5% NaHCO₃solution, collected the solid and washed with water (50 mL), dried invacuo to get compound 39-2 as a brown solid (4 g, yield 94%).

Method 40 Synthesis of 6-aminobenzo[d]oxazol-2(3H)-one (40-2)

Followed the same 2 step procedure described for the synthesis of5-aminobenzo[d]oxazol-2(3H)-one (39-2) in Method 39 above.

Method 41 Synthesis of 1-(5-bromo-2-methoxyphenyl)ethanone

Compound 41-2. To a solution of 41-1 (2.0 g, 13.32 mmol) in acetone (25mL) was added NBS (2.37 g, 13.32 mmol) and 1M HCl aq. (0.13 mL, 0.13mmol). The reaction mixture was stirred at room temperature for 3 h, andthen concentrated to dryness under reduced pressure. The residue wasdissolved with PE (40 mL) the resultant precipitate was filtered anddried in vacuum to afford 41-2 as a white solid (2.90 g, yield: 95%).

Example 2 GSNOR Assays

Various compounds were tested in vitro for their ability to inhibitGSNOR activity. Representative compounds and their corresponding GSNORactivity are described in a paragraph before Table 1 above. GSNORexpression and purification is described in Biochemistry 2000, 39,10720-10729.

GSNOR fermentation: Pre-cultures were grown from stabs of a GSNORglycerol stock in 2XYT media containing 100 ug/ml ampicillin after anovernight incubation at 37° C. Cells were then added to fresh 2XYT (4 L)containing ampicillin and grown to an OD (A₆₀₀) of 0.6-0.9 at 37° C.before induction. GSNOR expression was induced with 0.1% arabinose in anovernight incubation at 20° C.

GSNOR Purification: E. coli cell paste was lysed by nitrogen cavitationand the clarified lysate purified by Ni affinity chromatography on anAKTA FPLC (Amersham Pharmacia). The column was eluted in 20 mM Tris pH8.0/250 mM NaCl with a 0-500 mM imidazole gradient. Eluted GSNORfractions containing the Smt-GSNOR fusion were digested overnight withUlp-1 at 4° C. to remove the affinity tag then re-run on the Ni columnunder the same conditions. GSNOR was recovered in the flowthroughfraction and for crystallography is further purified by Q-Sepharose andHeparin flowthrough chromatography in 20 mM Tris pH 8.0, 1 mM DTT, 10 uMZnSO₄.

GSNOR assay: GSNO and Enzyme/NADH Solutions are made up fresh each day.The Solutions are filtered and allowed to warm to room temperature. GSNOSolution: 100 mM NaPO4 (pH 7.4), 0.480 mM GSNO. 396 μL of GSNO Solutionis added to a cuvette followed by 8 μL of test compound in DMSO (or DMSOonly for full reaction control) and mixed with the pipette tip.Compounds to be tested are made up at a stock concentration of 10 mM in100% DMSO. 2 fold serial dilutions are done in 100% DMSO. 8 μL of eachdilution are added to an assay so that the final concentration of DMSOin the assay is 1%. The concentrations of compounds tested range from100 to 0.003 μM. Enzyme/NADH Solution: 100 mM NaPO4 (pH 7.4), 0.600 mMNADH, 1.0 μg/mL GSNO Reductase. 396 μL of the Enzyme/NADH Solution isadded to the cuvette to start the reaction. The cuvette is placed in theCary 3E UV/Visible Spectrophotometer and the change in 340 nmabsorbance/min at 25° C. is recorded for 3 minutes. The assays are donein triplicate for each compound concentration. IC50's for each compoundare calculated using the standard curve analysis in the Enzyme KineticsModule of SigmaPlot.

Final assay conditions: 100 mM NaPO4, pH 7.4, 0.240 mM GSNO, 0.300 mMNADH, 0.5 μg/mL GSNO Reductase and 1% DMSO. Final volume: 800μL/cuvette.

Example 3 GSNOR Inhibition Assay in an In Vivo Animal Model

To demonstrate the influence of GSNOR inhibition, a mouse model ofasthma was used that was similar to a model previously shown to beinfluenced by GSNO reductase and bioavailable SNO's (Que et al.,Science, 2005). Que et al. demonstrated that following ova-albumin (OVA)challenge, wild type mice exhibiting bronchial reactivity have increasedlevels of GSNOR and have lungs that were depleted of SNO's. In contrastto wild-type mice, Que et al. demonstrated that mice with a geneticdeletion of GSNOR increased lung SNO's and were protected from OVAinduced airway hyper-reactivity.

In an effort to determine if similar observations would manifest ifGSNOR were inhibited pharmacologically by a GSNOR inhibitor, an OVAmouse model (i.e., the wild-type model of Que et al.) was used. In thisstudy, OVA sensitized mice were administered 1 mg/kg, 10 mg/kg or 30mg/kg of Compound 1 intravenously at 24 hours prior to being placed in awhole body plethysmograph (Buxco Research Systems, Wilmington, N.C.) andprovided with fresh air.

Subject animals were then challenged with an aerosol of increasingdosages of the bronchoconstrictive agent methacholine, a pharmacologicagent commonly used in determining the degree of bronchialhyper-reactivity in experimental subjects. In this study mice wereexposed to an increasing concentration of methacholine, each dose beingpresented for 3 minutes, during which time readings were taken. Doses ofmethacholine were 0 mg/ml, 5 mg/ml, 20 mg/ml, and 50 mg/ml. The degreeof bronchial hyper-reactivity was measured as the ‘Enhanced Pause’(Penh), a unit-less index of airway hyper-reactivity (Dohi et al., LabInvest. 79(12):1559-1571, 1999).

The administration of Compound 1 produced lower broncho-constrictiveresponses in these test animals compared with vehicle-only dosedanimals, These results are consistent with a greater level of bioactiveSNO's available to counter the broncho-constrictive methacholinechallenge.

Example 4 Efficacy of GSNORi in Experimental Asthma

Experimental Asthma Model

A mouse model of ovalbumin (OVA)-induced asthma was used to screen GSNORinhibitors for efficacy against methacholine (MCh)-inducedbronchoconstriction/airway hyper-reactivity. This is a widely used andwell characterized model that presents with an acute, allergic asthmaphenotype with similarities to human asthma. Efficacy of GSNORinhibitors were assessed using a prophylactic protocol in which GSNORinhibitors were administered prior to challenge with MCh.Bronchoconstriction in response to challenge with increasing doses ofMCh was assessed using whole body plethysmography (P_(enh); Buxco). Theamount of eosinophil infiltrate into the bronchioalveolar lavage fluid(BALF) was also determined as a measure of lung inflammation. The effectof GSNOR inhibitors were compared to vehicles and to Combivent (inhaled;IH) as the positive control.

Materials and Methods

Allergen Sensitization and Challenge Protocol

OVA (500 μg/ml) in PBS was mixed with equal volumes of 10% (w/v)aluminum potassium sulfate in distilled water and incubated for 60 min.at room temperature after adjustment to pH 6.5 using 10 N NaOH. Aftercentrifugation at 750×g for 5 min, the OVA/alum pellet was resuspendedto the original volume in distilled water. Mice received anintraperitoneal (IP) injection of 100 μg OVA (0.2 mL of 500 μg/mL innormal saline) complexed with alum on day 0. Mice were anesthetized byIP injection of a 0.2-mL mixture of ketamine and xylazine (0.44 and 6.3mg/mL, respectively) in normal saline and were placed on a board in thesupine position. Two hundred fifty micrograms (100 μl of a 2.5 mg/ml) ofOVA (on day 8) and 125 μg (50 μl of 2.5 mg/ml) OVA (on days 15, 18, and21) were placed on the back of the tongue of each animal.

Pulmonary Function Testing (Penh)

In vivo airway responsiveness to methacholine was measured 24 h afterthe last OVA challenge in conscious, freely moving, spontaneouslybreathing mice with whole body plethysmography using a Buxco chamber(Wilmington, N.C.). Mice were challenged with aerosolized saline orincreasing doses of methacholine (5, 20 and 50 mg/mL) generated by anultrasonic nebulizer for 2 min. The degree of bronchoconstriction wasexpressed as enhanced pause (P_(enh)), a calculated dimensionless value,which correlates with the measurement of airway resistance, impedance,and intrapleural pressure in the same mouse. P_(enh) readings were takenand averaged for 4 min. after each nebulization challenge. P_(enh) wascalculated as follows: P_(enh)=[(T_(e)/T_(r)−1)×(PEF/PIF)], where T_(e)is expiration time, T_(r) is relaxation time, PEF is peak expiratoryflow, and PIF is peak inspiratory flow×0.67 coefficient. The time forthe box pressure to change from a maximum to a user-defined percentageof the maximum represents the relaxation time. The T_(r) measurementbegins at the maximum box pressure and ends at 40%.

Eosinophil Infiltrate in BALF

After measurement of airway hyper-reactivity, the mice wereexsanguination by cardiac puncture, and then BALF was collected fromeither both lungs or from the right lung after tying off the left lungat the mainstem bronchus. Total BALF cells were counted from a 0.05 mLaliquot, and the remaining fluid is centrifuged at 200×g for 10 min at4° C. Cell pellets were resuspended in saline containing 10% BSA withsmears made on glass slides. Eosinophils were stained for 5 min. with0.05% aqueous eosin and 5% acetone in distilled water, rinsed withdistilled water, and counterstained with 0.07% methylene blue.

GSNOR Inhibitors and Controls

GSNOR inhibitors were reconstituted in phosphate buffered saline (PBS),pH 7.4, at concentrations ranging from 0.00005 to 3 mg/mL. GSNORinhibitors were administered to mice (10 mL/kg) as a single dose eitherintravenously (IV) or orally via gavage. Dosing was performed from 30min. to 24 h prior to MCh challenge. Effect of GSNOR inhibitors werecompared to PBS vehicle dosed in the same manner.

Combivent was used as the positive control in all studies. Combivent(Boehringer Ingelheim) was administered to the lung using the inhalerdevice supplied with the product, but adapted for administration tomice, using a pipet tip. Combivent was administered 48 h, 24 h, and 1 hprior to MCh challenge. Each puff (or dose) of Combivent provided a doseof 18 μg ipatropium bromide (IpBr) and 103 μg albuterol sulfate orapproximately 0.9 mg/kg IpBr and 5 mg/kg albuterol.

Statistical Analyses

Area under the curve values for P_(enh) across baseline, saline, andincreasing doses of MCh challenge were calculated using GraphPad Prism5.0 (San Diego, Calif.) and expressed as a percent of the respective (IVor orally administered) vehicle control. Statistical differences amongtreatment groups and the respective vehicle control group within eachstudy were calculated using one-way ANOVA, Dunnetts (JMP 8.0, SASInstitute, Cary, N.C.). A p value of <0.05 among the treatment groupsand the respective vehicle control group was considered significantlydifferent.

Results:

Compound 1 Results

Compound 1 administered intravenously (IV) was efficacious againstexperimental asthma as noted by attenuation of methacholine (MCh)induced bronchoconstriction and pulmonary inflammation. Significantefficacy with Compound 1 was observed with a single IV dose of 0.01mg/kg at 24 h prior to MCh. The area under the curve (AUC) for Penhresponse reported as percent of vehicle control (AUC=100%) was 42.1±2.8%(p<0.0001). Eosinophil infiltration into the bronchioalveolar lavagefluid (BALF) was reduced by 98% (p<0.0001). Significant efficacy withCompound 1 was also observed as early as 1 h (AUC=76.4±6.6; p=0.0082)and up to 48 h (AUC=64.4±55; p=<0.0001) prior to MCh at a single IV doseof 0.1 mg/kg. The ED50, the dose of Compound 1 demonstrating 50%reduction in Penh response, was 0.011±0.003 mg/kg.

Compound 2 Results

Compound 2 administered intravenously (IV) was efficacious againstexperimental asthma as noted by attenuation of methacholine (MCh)induced bronchoconstriction. Significant efficacy with Compound 2 wasobserved with a single IV dose of 0.01, 0.1, and 1 mg/kg at 24 h priorto MCh. The area under the curve (AUC) for Penh response reported aspercent of vehicle control (AUC=100%) was 65.3±6.5% (p=0.0002);50.5±6.3% (p<0.0001); and 41.7±5.2% (p<0.0001) for 0.01, 0.1, and 1mg/kg, respectively, of Compound 2.

Compound 3 Results

Compound 3 administered intravenously (IV) was efficacious againstexperimental asthma as noted by attenuation of methacholine (MCh)induced bronchoconstriction and pulmonary inflammation. Significantefficacy with Compound 3 was observed with a single IV dose of 1 mg/kgat 24 h prior to MCh. The area under the curve (AUC) for Penh responsereported as percent of vehicle control (AUC=100%) was 71.0±8.6%(p=0.0051). Eosinophil infiltration into the bronchioalveolar lavagefluid (BALF) was reduced by 46% (p=0.0002).

Compound 9 Results

Compound 9 administered intravenously (IV) or orally was efficaciousagainst experimental asthma as noted by attenuation of methacholine(MCh) induced bronchoconstriction and pulmonary inflammation.Significant efficacy with Compound 9 was observed with a single IV doseof 1 mg/kg at 24 h prior to MCh. The area under the curve (AUC) for Penhresponse reported as percent of vehicle control (AUC=100%) was 65.3±5.9%(p=0.0001). Eosinophil infiltration into the bronchioalveolar lavagefluid (BALF) was reduced by 92% (p<0.0001). Significant efficacy withCompound 9 was also observed with a single oral dose of 30 mg/kg at 24 hprior to MCh. The area under the curve (AUC) for Penh response reportedas percent of vehicle control (AUC=100%) was 24.6±3.0% (p<0.0001).Eosinophil infiltration into the bronchioalveolar lavage fluid (BALF)was reduced by 100% (p=0.0004).

Compound 12 Results

Compound 12 administered intravenously (IV) was efficacious againstexperimental asthma as noted by attenuation of methacholine (MCh)induced bronchoconstriction. Significant efficacy with Compound 12 wasobserved with a single IV dose of 0.1 and 1 mg/kg at 24 h prior to MCh.The area under the curve (AUC) for Penh response reported as percent ofvehicle control (AUC=100%) was 56.1±2.2% (p<0.0001) and 50.4±3.7%(p<0.0001) 0.1 and 1 mg/kg of Compound 7, respectively.

Compound 116 Results

Compound 116 administered intravenously (IV) or orally was efficaciousagainst experimental asthma as noted by attenuation of methacholine(MCh) induced bronchoconstriction and pulmonary inflammation.Significant efficacy with Compound 116 was observed with a single IVdose of 0.1, 1, and 10 mg/kg at 24 h prior to MCh. The area under thecurve (AUC) for Penh response reported as percent of vehicle control(AUC=100%) was 64.2±7.6% (p=0.0007); 60.2±7.9% (p=0.0002); and 40.7±2.4%(p<0.0001) for 0.1 mg/kg, 1 mg/kg, and 10 mg/kg, respectively, ofCompound 116. Eosinophil infiltration into the bronchioalveolar lavagefluid (BALF) was reduced by 79% (p=0.0064); 100% (p=0.0007); and 100%(p=0.0007) for 0.1 mg/kg, 1 mg/kg, and 10 mg/kg, respectively, ofCompound 116. Significant efficacy with Compound 116 was also observedas early as 30 min. (AUC=35.2±9.3; p<0.0001) prior to MCh at a single IVdose of 10 mg/kg. Eosinophil infiltration into the BALF was reduced by94% (p<0.0001). Significant efficacy with Compound 116 was also observedwith a single oral dose of 30 mg/kg at 24 h prior to MCh. The area underthe curve (AUC) for Penh response reported as percent of vehicle control(AUC=100%) was 26.7±1.4% (p<0.0001). Eosinophil infiltration into thebronchioalveolar lavage fluid (BALF) was reduced by 100% (p=0.0019).

Compound 136 Results

Compound 136 administered intravenously was efficacious againstexperimental asthma as noted by attenuation of methacholine (MCh)induced bronchoconstriction and pulmonary inflammation. Significantefficacy with Compound 136 was observed with a single IV dose of 1 mg/kgat 24 h prior to MCh. The area under the curve (AUC) for Penh responsereported as percent of vehicle control (AUC=100%) was 72.9±8.7%(p=0.0089). Eosinophil infiltration into the bronchioalveolar lavagefluid (BALF) was reduced by 61% (p<0.0001).

Compound 171 Results

Compound 171 administered intravenously (IV) was efficacious againstexperimental asthma as noted by attenuation of methacholine (MCh)induced bronchoconstriction and pulmonary inflammation. Significantefficacy with Compound 171 was observed with a single IV dose of 1 mg/kgat 24 h prior to MCh. The area under the curve (AUC) for Penh responsereported as percent of vehicle control (AUC=100%) was 78.7±8.1%(p=0.0323). Eosinophil infiltration into the bronchioalveolar lavagefluid (BALF) was reduced by 63% (p<0.0001).

It will be apparent to those skilled in the art that variousmodifications and variations can be made in the methods and compositionsof the present invention without departing from the spirit or scope ofthe invention.

1. A compound of formula I:

wherein Ar is selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl; R₁ is selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; R₂ is selected from the group consisting of halogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, cyano, nitro, CF₃, carbamoyl, C₁-C₆ alkylcarbamoyl, amino, C₁-C₆ alkylamino, C₁-C₆ dialkylamino, C₁-C₆ alkoxyl, and C₃-C₆ cycloalkoxyl; R₃ is selected from the group consisting of hydroxyl, carbamoyl, C₁-C₆ alkylcarbamoyl, sulfamoyl, C₁-C₆ alkylsulfamoyl, C₃-C₆ cycloalkyl, cyano, nitro, carboxyl, amino, aminomethyl, acetamido, acetamido-2-methyl, 2-methoxyacetamido, propionamido, tetrahydrofuran-2-ylmethoxy, CF₃, carboxyl, ureido, sulfamoylamino, C₁-C₆ alkylsulfonamido, 2-amino-2-oxoethyl, C₁-C₆ alkylamino, C₁-C₆ dialkylamino, arylamino, heteroarylamino, C₁-C₆ alkoxyl, C₃-C₆ cycloalkoxyl, 1H-imidazol-2-yl, oxazol-2-yl, thiazol-2-yl, methylcarbamoyl, dimethylcarbamoyl, methoxyethylcarbamoyl, hydroxyethylcarbamoyl, (dimethylamino)ethylcarbamoyl, pyridin-3-ylcarbamoyl, pyridin-4-yl-carbamoyl, 6-methoxypyridin-3-ylcarbamoyl, pyridazin-4-ylcarbamoyl, and pyrimidin-5-ylcarbamoyl; R₄ is selected from the group consisting of hydrogen, hydroxyl, halogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, cyano, nitro, carbamoyl, C₁-C₆ alkylcarbamoyl, sulfamoyl, C₁-C₆ alkyl sulfamoyl, amino, C₁-C₆ alkylamino, C₁-C₆ dialkylamino, C₁-C₆ alkoxyl, and C₃-C₆ cycloalkoxyl; n is 0-3; wherein Ar excludes substituted or unsubstituted indazol-3-yl and substituted or unsubstituted 1H-pyrazolo[3,4-b]pyridyl; with the following provisos: proviso Ia: when R₃ is carboxyl, methylsulfonamido, or sulfamoyl, then Ar cannot be phenyl, substituted or unsubstituted phenyl-(C₁-C₃)-alkyl, or phenyl-(C₂-C₆)-alkenyl; and proviso Ib: when R₂ and R₃ are both methoxy, then Ar cannot be phenyl, 4-methyl-phenyl, 4-methoxy-phenyl, 4-halo-phenyl, or thiophen-yl.
 2. The compound of claim 1 wherein: Ar is selected from the group consisting of phenyl, substituted phenyl, thiophen-yl, substituted thiophen-yl, pyridinyl, substituted pyridinyl, thiazolyl, substituted thiazolyl, pyrimidinyl, substituted pyrimidinyl, furanyl, substituted furanyl, bicyclic aryl, substituted bicyclic aryl, bicyclic heteroaryl, and substituted bicyclic heteroaryl; R₁ is selected from the group consisting of hydrogen and C₁-C₆ alkyl; R₂ is selected from the group consisting of halogen, C₁-C₆ alkyl, and CF₃; R₃ is selected from the group consisting of hydroxyl, carbamoyl, sulfamoyl, sulfamoylamino, C₁-C₆ alkoxy, amino, aminomethyl, acetamido, acetamido-2-methyl, 2-methoxyacetamido, propionamido, tetrahydrofuran-2-ylmethoxy, methylsulfamido, carboxyl, C₁-C₆ alkylamino, 1H-imidazol-2-yl, oxazol-2-yl, thiazol-2-yl, methylcarbamoyl, dimethylcarbamoyl, methoxyethylcarbamoyl, hydroxyethylcarbamoyl, (dimethylamino)ethylcarbamoyl, pyridin-3-ylcarbamoyl, pyridin-4-yl-carbamoyl, 6-methoxypyridin-3-ylcarbamoyl, pyridazin-4-ylcarbamoyl, and pyrimidin-5-ylcarbamoyl; R₄ is selected from the group consisting of hydrogen and C₁-C₆ alkyl; and n is
 1. 3. The compound of claim 2 wherein Ar is selected from the group consisting of phenyl, substituted phenyl, aryl-phenyl, substituted aryl-phenyl, heteroaryl-phenyl, substituted heteroaryl-phenyl, thiophen-yl, substituted thiophen-yl, aryl-thiophen-yl, substituted aryl-thiophen-yl, heteroaryl-thiophen-yl, substituted heteroaryl-thiophen-yl, pyridinyl, substituted pyridinyl, aryl-pyridinyl, substituted aryl-pyridinyl, heteroaryl-pyridinyl, substituted heteroaryl-pyridinyl, thiazolyl, substituted thiazolyl, aryl-thiazolyl; substituted aryl-thiazolyl; heteroaryl-thiazolyl; substituted heteroaryl-thiazolyl, pyrimidinyl, substituted pyrimidinyl, aryl-pyrimidinyl, substituted aryl-pyrimidinyl, heteroaryl-pyrimidinyl, substituted heteroaryl-pyrimidinyl, furanyl, substituted furanyl, aryl-furanyl, substituted aryl-furanyl, heteroaryl-furanyl, and substituted heteroaryl-furanyl.
 4. The compound of claim 2 wherein Ar is phenyl, thiophen-yl, thiazolyl, pyridinyl, pyrimidinyl, or furanyl having 0, 1, 2, or 3 substitutions, wherein such substitutions are independently selected from the group consisting of hydrogen, hydroxyl, halogen, C₁-C₆ alkoxy, amino, cyano, C₁-C₆ alkyl, imidazolyl, methyl imidazolyl, ethyl imidazolyl, furanyl, methylthio, nitro, triazolyl, tetrazolyl, carbamoyl, pyrazolyl, trifluoromethoxy, trifluoromethyl, 2-amino-2oxoethoxy, ureido, morpholino, pyridinyl, pyrrolyl, methyl sulfonamido, carbamoyl phenyl, 6-oxo-1,6-dihydropyridinyl, 3,5-dimethylisoxazolyl, carboxymethoxy, hydroxyacetamido, methoxyacetamido, sulfamoyl, piperazinyl, oxoimidazolidinyl, methylsulfinyl, methylsulfonyl, pyrrolidinyl, piperidinyl, methylpyrazolyl, phenyl, thiazolyl, hydroxycarbamoyl, cyclopropylimidazolyl, carboxy, methylamino, methoxymethyl, dimethylamino, hydroxymethylimidazolyl, oxoxazolidinyl, formamido, hydroxyphenyl, and thiophen-yl.
 5. The compound of claim 2 wherein Ar is selected from the group consisting of 4-(1H-imidazol-1-yl)phenyl, 5-(1H-imidazol-1-yl)thiophen-2-yl, 4-(2-methyl-1H-imidazol-1-yl)phenyl, thiazol-5-yl, 4-hydroxyphenyl, 5-bromothiophen-2-yl, 4-methoxyphenyl, 4-aminophenyl, 4-bromophenyl, 4-(furan-3-yl)phenyl, phenyl, 3-chloro-4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-cyanophenyl, 3-chloro-4-hydroxyphenyl, 4-methoxy-3-methylphenyl, 4-iodophenyl, 3-methoxyphenyl, 6-methoxypyridin-3-yl, benzo[d]thiazol-6-yl, 4-(methylthio)phenyl, 4-nitrophenyl, 4-(4H-1,2,4-triazol-4-yl)phenyl, 4-(2H-tetrazol-5-yl)phenyl, benzo[d][1,3]dioxol-5-yl, 6-(1H-imidazol-1-yl)pyridin-3-yl, 5-carbamoylthiophen-2-yl, 4-(1H-pyrazol-4-yl)phenyl, 4-(trifluoromethoxy)phenyl, 4-carbamoylphenyl, 4-(trifluoromethyl)phenyl, 4-(1H-1,2,4-triazol-1-yl)phenyl, 4-(1H-pyrazol-1-yl)phenyl, 4-(2-amino-2-oxoethoxy)phenyl, 4-(1-methyl-1H-pyrazol-4-yl)phenyl, 4-(1H-tetrazol-1-yl)phenyl, 4-(4-methyl-1H-imidazol-1-yl)phenyl, 4-ureidophenyl, 4-morpholinophenyl, 4-(2H-tetrazol-5-yl)phenyl, 4-(pyridin-4-yl)phenyl, 4-(1H-pyrrol-1-yl)phenyl, 4-(methylsulfonamido)phenyl, 1H-1,2,3-triazol-1-yl)phenyl, naphthalen-2-yl, 3′-carbamoylbiphenyl-4-yl, 4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl, 4-(3,5-dimethylisoxazol-4-yl)phenyl, 4-(pyridin-3-yl)phenyl, 4-(carboxymethoxy)phenyl, 4-(2-hydroxyacetamido)phenyl, 4-(2-methoxyacetamido)phenyl, 4-sulfamoylphenyl, 4-(piperazin-1-yl)phenyl, 4-(2-oxoimidazolidin-1-yl)phenyl, 4-ethoxyphenyl, 4-(methylsulfinyl)phenyl, 4-(2-ethyl-1H-imidazol-1-yl)phenyl, 4-(furan-2-yl)phenyl, 4-(methylsulfonyl)phenyl, 4-(pyrrolidin-1-yl)phenyl, 4-(piperidin-1-yl)phenyl, 4-(1-methyl-1H-pyrazol-5-yl)phenyl, 5-(2-methyl-1H-imidazol-1-yl)thiophen-2-yl, 4-(furan-3-yl)phenyl, 2-methoxypyrimidin-5-yl, 2-methyl-4-(methylsulfonamido)phenyl, 4-amino-3-chlorophenyl, 3,4-difluorophenyl, 2,4-difluorophenyl, 4-chlorophenyl, 4-bromothiophen-2-yl, biphenyl-4-yl, 2-(1H-imidazol-1-yl)pyrimidin-5-yl, 4-fluoro-3-methoxyphenyl, 3-cyano-4-fluorophenyl, 4-carbamoyl-2-methylphenyl, 4-methoxy-2-methylphenyl, 4-chloro-2-fluorophenyl, 4-fluorophenyl, 4-fluoro-2-methylphenyl, 4-chloro-2-(trifluoromethyl)phenyl, 4-chloro-2-methoxyphenyl, 4-cyano-3-fluorophenyl, 2-chloro-4-methoxyphenyl, 4-(1H-imidazol-1-yl)thiophen-2-yl, 3,5-dimethyl-4-nitrophenyl, 4-amino-3,5-dimethylphenyl, 2-(1H-imidazol-1-yl)thiazol-4-yl, 2-ethoxy-4-fluorophenyl, 4-methoxy-2-(trifluoromethyl)phenyl, 4-fluoro-2-methoxyphenyl, 4-(thiazol-5-yl)phenyl, 4-chloro-3-fluorophenyl, 4-(hydroxycarbamoyl)phenyl, 3-fluoro-4-(1H-imidazol-1-yl)phenyl, 3-fluoro-4-(2-methyl-1H-imidazol-1-yl)phenyl, 4-chloro-2-ethoxyphenyl, 5-bromo-2-methoxyphenyl, 4-(2-cyclopropyl-1H-imidazol-1-yl)phenyl, 4-(2-methyl-1H-imidazol-1-yl)thiophen-2-yl, 4-bromo-2-methoxyphenyl, 2-methoxy-4-(2-methyl-1H-imidazol-1-yl)phenyl, 4-chloro-2-hydroxyphenyl, 5-bromothiophen-3-yl, 4-hydroxy-3-methylphenyl, 2-carbamoyl-4-chlorophenyl, 2-acetamido-4-chlorophenyl, 2-methoxyphenyl, benzoic acid, 2,4-dimethoxyphenyl, 4-chloro-2-propoxyphenyl, 4-chloro-2-(2-methoxyacetamido)phenyl, 4-chloro-2-(methylsulfonamido)phenyl, 4-chloro-2-(methylamino)phenyl, 4-chloro-2-(methoxymethyl)phenyl, 4-hydroxy-2-methoxyphenyl, 4-chloro-2-(dimethylamino)phenyl, 4-(2-(hydroxymethyl)-1H-imidazol-1-yl)phenyl, 4-(2-oxooxazolidin-3-yl)phenyl)-1H-pyrrol-2-yl, 4-(1H-imidazol-1-yl)-2-methoxyphenyl, 5-(2-methyl-1H-imidazol-1-yl)thiophen-3-yl, 5-chlorothiophen-2-yl, 5-bromothiazol-2-yl, 4-bromothiazol-2-yl, 5-(2-ethyl-1H-imidazol-1-yl)thiophen-2-yl, 4-chloro-2-formamidophenyl, 3-chlorothiophen-2-yl, 4-formamido-2-methoxyphenyl, 3-bromo-5-methoxythiophen-2-yl, 5-(4-hydroxyphenyl)thiophen-2-yl, 4-(thiophen-3-yl)phenyl, 5-(1H-imidazol-1-yl)furan-2-yl, 4-chlorothiophen-2-yl, 5-bromo-4-chlorothiophen-2-yl, 5-(2-methyl-1H-imidazol-1-yl)furan-2-yl, and 5-bromofuran-2-yl.
 6. The compound of claim 2 wherein Ar is selected from the group consisting of 4-(1H-imidazol-1-yl)phenyl, 5-(1H-imidazol-1-yl)thiophen-2-yl, 4-(2-methyl-1H-imidazol-1-yl)phenyl, thiazol-5-yl, 4-hydroxyphenyl, 5-bromothiophen-2-yl, 4-methoxyphenyl, 4-aminophenyl, 4-bromophenyl, 4-(furan-3-yl)phenyl, 3-chloro-4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-cyanophenyl, 3-chloro-4-hydroxyphenyl, 4-methoxy-3-methylphenyl, 4-iodophenyl, 3-methoxyphenyl, 6-methoxypyridin-3-yl, benzo[d]thiazol-6-yl, 4-(methylthio)phenyl, 4-nitrophenyl, 4-(4H-1,2,4-triazol-4-yl)phenyl, 4-(2H-tetrazol-5-yl)phenyl, benzo[d][1,3]dioxol-5-yl, 6-(1H-imidazol-1-yl)pyridin-3-yl, 5-carbamoylthiophen-2-yl, 4-(1H-pyrazol-4-yl)phenyl, 4-(trifluoromethoxy)phenyl, 4-carbamoylphenyl, 4-(trifluoromethyl)phenyl, 4-(1H-1,2,4-triazol-1-yl)phenyl, 4-(1H-pyrazol-1-yl)phenyl, 4-(2-amino-2-oxoethoxy)phenyl, 4-(1-methyl-1H-pyrazol-4-yl)phenyl, 4-(1H-tetrazol-1-yl)phenyl, 4-(4-methyl-1H-imidazol-1-yl)phenyl, 4-ureidophenyl, 4-morpholinophenyl, 4-(2H-tetrazol-5-yl)phenyl, 4-(pyridin-4-yl)phenyl, 4-(1H-pyrrol-1-yl)phenyl, 4-(methylsulfonamido)phenyl, 1H-1,2,3-triazol-1-yl)phenyl, naphthalen-2-yl, 3′-carbamoylbiphenyl-4-yl, 4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl, 4-(3,5-dimethylisoxazol-4-yl)phenyl, 4-(pyridin-3-yl)phenyl, 4-(carboxymethoxy)phenyl, 4-(2-hydroxyacetamido)phenyl, 4-(2-methoxyacetamido)phenyl, 4-sulfamoylphenyl, 4-(piperazin-1-yl)phenyl, 4-(2-oxoimidazolidin-1-yl)phenyl, 4-ethoxyphenyl, 4-(methylsulfinyl)phenyl, 4-(2-ethyl-1H-imidazol-1-yl)phenyl, 4-(furan-2-yl)phenyl, 4-(methylsulfonyl)phenyl, 4-(pyrrolidin-1-yl)phenyl, 4-(piperidin-1-yl)phenyl, 4-(1-methyl-1H-pyrazol-5-yl)phenyl, 5-(2-methyl-1H-imidazol-1-yl)thiophen-2-yl, 4-(furan-3-yl)phenyl, 2-methoxypyrimidin-5-yl, 2-methyl-4-(methylsulfonamido)phenyl, 4-amino-3-chlorophenyl, 3,4-difluorophenyl, 2,4-difluorophenyl, 4-chlorophenyl, 4-bromothiophen-2-yl, biphenyl-4-yl, 2-(1H-imidazol-1-yl)pyrimidin-5-yl, 4-fluoro-3-methoxyphenyl, 3-cyano-4-fluorophenyl, 4-carbamoyl-2-methylphenyl, 4-methoxy-2-methylphenyl, 4-chloro-2-fluorophenyl, 4-fluorophenyl, 4-fluoro-2-methylphenyl, 4-chloro-2-(trifluoromethyl)phenyl, 4-chloro-2-methoxyphenyl, 4-cyano-3-fluorophenyl, 2-chloro-4-methoxyphenyl, 4-(1H-imidazol-1-yl)thiophen-2-yl, 3,5-dimethyl-4-nitrophenyl, 4-amino-3,5-dimethylphenyl, 2-(1H-imidazol-1-yl)thiazol-4-yl, 2-ethoxy-4-fluorophenyl, 4-methoxy-2-(trifluoromethyl)phenyl, 4-fluoro-2-methoxyphenyl, 4-(thiazol-5-yl)phenyl, 4-chloro-3-fluorophenyl, 4-(hydroxycarbamoyl)phenyl, 3-fluoro-4-(1H-imidazol-1-yl)phenyl, 3-fluoro-4-(2-methyl-1H-imidazol-1-yl)phenyl, 4-chloro-2-ethoxyphenyl, 5-bromo-2-methoxyphenyl, 4-(2-cyclopropyl-1H-imidazol-1-yl)phenyl, 4-(2-methyl-1H-imidazol-1-yl)thiophen-2-yl, 4-bromo-2-methoxyphenyl, 2-methoxy-4-(2-methyl-1H-imidazol-1-yl)phenyl, 4-chloro-2-hydroxyphenyl, 5-bromothiophen-3-yl, 4-hydroxy-3-methylphenyl, 2-carbamoyl-4-chlorophenyl, 2-acetamido-4-chlorophenyl, 2-methoxyphenyl, benzoic acid, 2,4-dimethoxyphenyl, 4-chloro-2-propoxyphenyl, 4-chloro-2-(2-methoxyacetamido)phenyl, 4-chloro-2-(methylsulfonamido)phenyl, 4-chloro-2-(methylamino)phenyl, 4-chloro-2-(methoxymethyl)phenyl, 4-hydroxy-2-methoxyphenyl, 4-chloro-2-(dimethylamino)phenyl, 4-(2-(hydroxymethyl)-1H-imidazol-1-yl)phenyl, 4-(2-oxooxazolidin-3-yl)phenyl)-1H-pyrrol-2-yl, 4-(1H-imidazol-1-yl)-2-methoxyphenyl, 5-(2-methyl-1H-imidazol-1-yl)thiophen-3-yl, 5-chlorothiophen-2-yl, 5-bromothiazol-2-yl, 4-bromothiazol-2-yl, 5-(2-ethyl-1H-imidazol-1-yl)thiophen-2-yl, 4-chloro-2-formamidophenyl, 3-chlorothiophen-2-yl, 4-formamido-2-methoxyphenyl, 3-bromo-5-methoxythiophen-2-yl, 5-(4-hydroxyphenyl)thiophen-2-yl, 4-(thiophen-3-yl)phenyl, 5-(1H-imidazol-1-yl)furan-2-yl, 4-chlorothiophen-2-yl, 5-bromo-4-chlorothiophen-2-yl, 5-(2-methyl-1H-imidazol-1-yl)furan-2-yl, and 5-bromofuran-2-yl.
 7. The compound of claim 4 selected from the group consisting of: 3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(5-(1H-imidazol-1-yl)thiophen-2-yl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(thiazol-5-yl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-hydroxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(5-bromothiophen-2-yl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2,6-dimethylphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-hydroxy-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-chlorophenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-aminophenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-bromophenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(furan-3-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-methoxyphenyl)-1-(2-methyl-4-sulfamoylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-phenyl-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(3-chloro-4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-cyanophenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(3-chloro-4-hydroxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-ethylphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-methoxy-3-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-iodophenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(3-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(6-methoxypyridin-3-yl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(benzo[d]thiazol-6-yl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(methylthio)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-nitrophenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-amino-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-(4H-1,2,4-triazol-4-yl)phenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-(2H-tetrazol-5-yl)phenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-methoxy-2-methylphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(benzo[d][1,3]dioxol-5-yl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-bromophenyl)-1-(4-hydroxy-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(6-(1H-imidazol-1-yl)pyridin-3-yl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(5-carbamoylthiophen-2-yl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-(1H-pyrazol-4-yl)phenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(trifluoromethoxy)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-carbamoylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(trifluoromethyl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-(1H-1,2,4-triazol-1-yl)phenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-(1H-pyrazol-1-yl)phenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-(2-amino-2-oxoethoxy)phenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-(1H-tetrazol-1-yl)phenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(4-methyl-1H-imidazol-1-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-ureidophenyl)-1H-pyrrol-2-yl)propanoic acid; 4-(2-(benzo[d][1,3]dioxol-5-yl)-5-(2-carboxyethyl)-1H-pyrrol-1-yl)-3-methylbenzoic acid; 3-(1-(4-amino-2-methylphenyl)-5-(4-bromophenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-morpholinophenyl)-1H-pyrrol-2-yl)propanoic acid; 4-(2-(4-(2H-tetrazol-5-yl)phenyl)-5-(2-carboxyethyl)-1H-pyrrol-1-yl)-3-methylbenzoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(pyridin-4-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-(1H-pyrrol-1-yl)phenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-hydroxy-2,5-dimethylphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(methylsulfonamido)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-(1H-1,2,3-triazol-1-yl)phenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(naphthalen-2-yl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(3′-carbamoylbiphenyl-4-yl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(pyridin-3-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(carboxymethoxy)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(2-hydroxyacetamido)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(2-methoxyacetamido)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-sulfamoylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(piperazin-1-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(2-oxoimidazolidin-1-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-ethoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(methylsulfinyl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(2-ethyl-1H-imidazol-1-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-(aminomethyl)-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-(1H-imidazol-2-yl)-2-methylphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(furan-2-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-(dimethylcarbamoyl)-2-methylphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-methoxyphenyl)-1-(2-methyl-4-(methylcarbamoyl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-(2-methoxyethylcarbamoyl)-2-methylphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-(2-hydroxyethylcarbamoyl)-2-methylphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-methoxyphenyl)-1-(2-methyl-4-(oxazol-2-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(methylsulfonyl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-hydroxy-2-methylphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(2-chloro-4-hydroxyphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-hydroxy-2,3-dimethylphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(pyrrolidin-1-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(piperidin-1-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(1-methyl-1H-pyrazol-5-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid; ethyl 3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoate; ethyl 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-1H-pyrrol-2-yl)propanoate; ethyl 3-(1-(4-carbamoyl-2-methylphenyl)-5-(5-(2-methyl-1H-imidazol-1-yl)thiophen-2-yl)-1H-pyrrol-2-yl)propanoate; ethyl 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(furan-3-yl)phenyl)-1H-pyrrol-2-yl)propanoate; ethyl 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-cyanophenyl)-1H-pyrrol-2-yl)propanoate; ethyl 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(furan-2-yl)phenyl)-1H-pyrrol-2-yl)propanoate; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(2-methoxypyrimidin-5-yl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(2-methyl-4-(methylsulfonamido)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-acetamido-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-hydroxy-2-(trifluoromethyl)phenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-methoxyphenyl)-1-(4-((tetrahydrofuran-2-yl)methoxy)-2-(trifluoromethyl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-(trifluoromethyl)phenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(2-methyl-4-propionamidophenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-(2-methoxyacetamido)-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-amino-3-chlorophenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(3,4-difluorophenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(2,4-difluorophenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-chlorophenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-bromothiophen-2-yl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(biphenyl-4-yl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-fluorophenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(2-(1H-imidazol-1-yl)pyrimidin-5-yl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-fluoro-3-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(3-cyano-4-fluorophenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-carbamoyl-3-fluorophenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-methoxy-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-methoxyphenyl)-1-(2-methyl-4-(thiazol-2-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-chloro-2-fluorophenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-fluorophenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-fluoro-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-chloro-2-(trifluoromethyl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-chloro-2-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-cyano-3-fluorophenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(2-chloro-4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-(2-(dimethylamino)ethylcarbamoyl)-2-methylphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-(1H-imidazol-1-yl)thiophen-2-yl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(3,5-dimethyl-4-nitrophenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-amino-3,5-dimethylphenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(2-(1H-imidazol-1-yl)thiazol-4-yl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(2-ethoxy-4-fluorophenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-methoxy-2-(trifluoromethyl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-fluoro-2-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-bromophenyl)-1-(2-methyl-4-(pyridin-3-ylcarbamoyl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-bromophenyl)-1-(4-(6-methoxypyridin-3-ylcarbamoyl)-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-methoxyphenyl)-1-(4-(6-methoxypyridin-3-ylcarbamoyl)-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(thiazol-5-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-chloro-3-fluorophenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(hydroxycarbamoyl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-bromophenyl)-1-(2-methyl-4-(pyridin-4-ylcarbamoyl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-methoxyphenyl)-1-(2-methyl-4-(pyridazin-4-ylcarbamoyl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-methoxyphenyl)-1-(2-methyl-4-(pyridin-3-ylcarbamoyl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(5-(2-methyl-1H-imidazol-1-yl)thiophen-2-yl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(3-fluoro-4-(1H-imidazol-1-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-methoxyphenyl)-1-(2-methyl-4-(pyrimidin-5-ylcarbamoyl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-1-(2-methyl-4-(methylsulfonamido)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(3-fluoro-4-(2-methyl-1H-imidazol-1-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-chloro-2-ethoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(5-bromo-2-methoxyphenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(2-cyclopropyl-1H-imidazol-1-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(2-methyl-1H-imidazol-1-yl)thiophen-2-yl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-bromo-2-methoxyphenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(2-methoxy-4-(2-methyl-1H-imidazol-1-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-acetamido-2-methylphenyl)-5-(4-bromophenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-bromophenyl)-1-(4-(2-methoxyacetamido)-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-chloro-2-hydroxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(5-bromothiophen-3-yl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-hydroxy-3-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(2-carbamoyl-4-chlorophenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(2-acetamido-4-chlorophenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(2-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 4-(1-(4-carbamoyl-2-methylphenyl)-5-(2-carboxyethyl)-1H-pyrrol-2-yl)benzoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(2,4-dimethoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-chloro-2-propoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-chloro-2-(2-methoxyacetamido)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-chloro-2-(methylsulfonamido)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-chloro-2-(methylamino)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-chloro-2-(methoxymethyl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-hydroxy-2-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-chloro-2-(dimethylamino)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(2-(hydroxymethyl)-1H-imidazol-1-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(2-oxooxazolidin-3-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-(1H-imidazol-1-yl)-2-methoxyphenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(5-(2-methyl-1H-imidazol-1-yl)thiophen-3-yl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(5-chlorothiophen-2-yl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(5-bromothiazol-2-yl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-(2-methyl-1H-imidazol-1-yl)thiophen-2-yl)-1-(2-methyl-4-(methylsulfonamido)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(5-(2-methyl-1H-imidazol-1-yl)thiophen-2-yl)-1-(2-methyl-4-(methylsulfonamido)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-acetamido-2-methylphenyl)-5-(4-chloro-2-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-bromothiazol-2-yl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(5-bromothiophen-2-yl)-1-(2-methyl-4-(methylsulfonamido)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-acetamido-2-methylphenyl)-5-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-chloro-2-methoxyphenyl)-1-(2-methyl-4-(methylsulfonamido)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(5-(2-ethyl-1H-imidazol-1-yl)thiophen-2-yl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-chloro-2-formamidophenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(3-chlorothiophen-2-yl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-formamido-2-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(3-bromo-5-methoxythiophen-2-yl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(5-(4-hydroxyphenyl)thiophen-2-yl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-bromothiophen-2-yl)-1-(2-methyl-4-(methylsulfonamido)phenyl)-1H-pyrrol-2-yl)propanoic acid; 2-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(thiophen-3-yl)phenyl)-1H-pyrrol-2-yl)acetic acid; 3-(5-(4-bromophenyl)-1-(2-methyl-4-(methylsulfonamido)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(5-(1H-imidazol-1-yl)furan-2-yl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-chloro-2-methoxyphenyl)-1-(2-methyl-4-sulfamoylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-chlorothiophen-2-yl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(5-bromo-4-chlorothiophen-2-yl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-bromothiophen-2-yl)-1-(2-methyl-4-sulfamoylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-methoxyphenyl)-1-(2-methyl-4-(pyridin-4-ylcarbamoyl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-2-methylphenyl)-5-(5-(2-methyl-1H-imidazol-1-yl)furan-2-yl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(5-bromofuran-2-yl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(5-(2-methyl-1H-imidazol-1-yl)thiophen-2-yl)-1-(2-methyl-4-sulfamoylphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-bromophenyl)-1-(2-methyl-4-(sulfamoylamino)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-methoxyphenyl)-1-(2-methyl-4-(sulfamoylamino)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-chloro-2-methoxyphenyl)-1-(2-methyl-4-(sulfamoylamino)phenyl)-1H-pyrrol-2-yl)propanoic acid; and 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)butanoic acid.
 8. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 together with a pharmaceutically accepted carrier or excipient.
 9. A method of treatment of a disease or condition which comprises administering a therapeutically effective amount of a compound of formula I as defined in claim 1 to a patient in need thereof.
 10. A compound of formula II:

wherein Ar is selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl; R₁ is selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; X₁-X₄ is independently selected from the group consisting of C and N; R₅ is selected from the group consisting of hydrogen, hydroxyl, halogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, cyano, nitro, carbamoyl, C₁-C₆ alkylcarbamoyl, carboxyl, C₁-C₆ alkylhydroxy, sulfamoyl, C₁-C₆ alkylsulfamoyl, amino, C₁-C₆ alkylamino, C₁-C₆ dialkylamino, C₁-C₆ alkoxyl, and C₃-C₆ cycloalkoxyl; R₆ is selected from the group consisting of halogen, hydroxyl, carbamoyl, substituted carbamoyl, C₁-C₆ alkylcarbamoyl, sulfamoyl, C₁-C₆ alkylsulfamoyl, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, cyano, nitro, amino, CF₃, carboxyl, ureido, sulfamoylamino, 2-amino-2-oxoethyl, C₁-C₆ alkylamino, C₁-C₆ dialkylamino, arylamino, heteroarylamino, C₁-C₆ alkoxyl, C₃-C₆ cycloalkoxyl, 1H-imidazol-1-yl, and 2-methyl-1H-imidazol-1-yl; or alternatively R₅ and R₆ together form a substituted or unsubstituted 5 or 6 membered heterocyclic ring containing up to 2 heteroatoms chosen from O, N or S; R₇ is selected from the group consisting of hydrogen, hydroxyl, halogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, cyano, nitro, carbamoyl, C₁-C₆ alkylcarbamoyl, sulfamoyl, C₁-C₆ alkylsulfamoyl, amino, C₁-C₆ alkylamino, C₁-C₆ dialkylamino, C₁-C₆ alkoxyl, and C₃-C₆ cycloalkoxyl; n is 0-3; wherein R₅ can be hydrogen only when at least one of X₁-X₄ is N; and further wherein, X₁ and X₃ must be CH or N unless R₅ and R₆ together form a 5 or 6 membered heterocyclic ring or at least one of X₁-X₄ is N; and wherein Ar excludes substituted or unsubstituted indazol-3-yl and substituted or unsubstituted 1H-pyrazolo[3,4-b]pyridyl; with the following provisos: proviso IIa: when all X are C and one of R₅, R₆, or R₇ are carboxyl, methylsulfonamido, or sulfamoyl, then Ar cannot be phenyl, substituted or unsubstituted phenyl-(C₁-C₃)-alkyl, or phenyl-(C₂-C₆)-alkenyl; and proviso IIb: when all X are C and one of R₅, R₆, or R₇ are independently selected from the group consisting of halogen or methyl, then Ar cannot be 4-hydroxyphenyl or 4-C₁-C₆ acyl-oxy-phenyl; and proviso IIc: when all X are C and R₅ is methyl, Cl, hydroxyl, trifluoromethyl and R₆ is methyl, methyoxy, carboxyethyl, Cl, or carboxypropyl, and n is 1, then Ar cannot be phenyl, 4-methyl-phenyl, 4-methoxy-phenyl, 4-halo-phenyl, or thiophen-yl; and proviso IId: when all X are C and R₅ and R₆ together form a heterocyclic ring and the resulting bicyclic ring system is benzo[d]thiazol substituted at the 2 position with C₁-C₃ alkyl, then Ar cannot be phenyl, 4-F-phenyl, 4-methoxy-phenyl, or thiophen-yl.
 11. The compound of claim 10 wherein: Ar is selected from the group consisting of phenyl, substituted phenyl, thiophen-yl, substituted thiophen-yl, pyridinyl, substituted pyridinyl, thiazolyl, and substituted thiazolyl.
 12. The compound of claim 10 selected from the group consisting of: 3-(5-(4-methoxyphenyl)-1-(1-oxoisoindolin-5-yl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-3-methoxyphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(1H-benzo[d]imidazol-6-yl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-3-hydroxyphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(5-carbamoylpyridin-2-yl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(3-chloro-4-hydroxyphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(6-carbamoylpyridin-3-yl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-methoxyphenyl)-1-(1-oxo-1,3-dihydroisobenzofuran-5-yl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(1H-benzo[d]imidazol-6-yl)-5-phenyl-1H-pyrrol-2-yl)propanoic acid; 3-(1-(1,3-dioxoisoindolin-5-yl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(1H-indazol-5-yl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-methoxyphenyl)-1-(6-oxo-1,6-dihydropyridin-3-yl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(2-aminobenzo[d]thiazol-6-yl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-hydroxy-3-methylphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(1H-indazol-6-yl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-5-phenyl-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-methoxyphenyl)-1-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-methoxyphenyl)-1-(quinolin-6-yl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-hydroxy-3,5-dimethylphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(5-(1H-imidazol-1-yl)pyridin-2-yl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(5-methyl-1H-benzo[d]imidazol-6-yl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(3-chloro-4-cyanophenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoyl-3-chlorophenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(isoquinolin-6-yl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(isoquinolin-7-yl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(1H-indol-5-yl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(2-oxoindolin-5-yl)-5-phenyl-1H-pyrrol-2-yl)propanoic acid; 3-(1-(3-cyano-4-fluorophenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-hydroxy-3-(methoxycarbonyl)phenyl)-5-phenyl-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-hydroxy-3-(methoxycarbonyl)phenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(3-fluoro-4-hydroxyphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-hydroxy-3-(hydroxymethyl)phenyl)-5-phenyl-1H-pyrrol-2-yl)propanoic acid; 3-(1-(3-aminobenzo[d]isoxazol-6-yl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 5-(2-(2-carboxyethyl)-5-phenyl-1H-pyrrol-1-yl)-2-hydroxybenzoic acid; 3-(1-(3-aminobenzo[d]isoxazol-5-yl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-hydroxy-3-(hydroxymethyl)phenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-1-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-1H-pyrrol-2-yl)propanoic acid; and 3-(5-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-1-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-1H-pyrrol-2-yl)propanoic acid.
 13. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 10 together with a pharmaceutically accepted carrier or excipient.
 14. A method of treatment of a disease or condition which comprises administering a therapeutically effective amount of a compound of formula II as defined in claim 10 to a patient in need thereof.
 15. A method of making a compound of formula II as defined in claim
 10. 16. A compound of formula III:

Ar is selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl; R₁ is selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; X₅-X₈ are independently selected from the group consisting of N, C and S, wherein at least one X must be N or S; R₈ and R₉ are independently selected from the group consisting of hydrogen, halogen, hydroxyl, carbamoyl, substituted carbamoyl, sulfamoyl, substituted sulfamoyl, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, cyano, nitro, amino, CF₃, carboxyl, ureido, sulfamoylamino, 2-amino-2-oxoethyl, C₁-C₆ alkylamino, C₁-C₆ dialkylamino, arylamino, heteroarylamino, C₁-C₆ alkoxyl, C₃-C₆ cycloalkoxyl, aryl, aryloxyl, substituted aryl, heteroaryl, substituted heteroaryl, and null if X₅-X₈ are all N; n is 0-3; wherein Ar excludes substituted or unsubstituted indazol-3-yl and substituted or unsubstituted 1H-pyrazolo[3,4-b]pyridyl.
 17. The compound of claim 16 wherein Ar is selected from the group consisting of phenyl, substituted phenyl, thiophen-yl, substituted thiophen-yl, pyridinyl, substituted pyridinyl, thiazolyl, substituted thiazolyl, bicyclic aryl, substituted bicyclic aryl, bicyclic heteroaryl, and substituted bicyclic heteroaryl.
 18. The compound of claim 16 selected from the group consisting of: 3-(1-(5-carbamoylthiophen-2-yl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(5-carbamoylthiazol-2-yl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoylthiophen-2-yl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(5-carbamoylthiophen-3-yl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-(2-amino-2-oxoethyl)thiazol-2-yl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; and 3-(1-(4-carbamoylthiazol-2-yl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid.
 19. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 16 together with a pharmaceutically accepted carrier or excipient.
 20. A method of treatment of a disease or condition which comprises administering a therapeutically effective amount of a compound of formula III as defined in claim 16 to a patient in need thereof.
 21. A method of making a compound of formula III as defined in claim
 16. 22. A compound of formula IV:

Ar is selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl; R₁ is selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; R₁₀ is hydroxyl, carbamoyl, ureido, sulfamoylamino, 2-amino-2-oxoethyl, acetyl, hydroxyethyl, pyridin-3-ylamino, pyridin-4-ylamino, 1-methylpyrrolidin-3-yloxy, trifluoroacetyl, imidazol-1-yl, acetamido, methylsulfamido, 2-oxooxazolidin-3-yl, 2-hydroxyethylamino, and methylcarbamoyl; n is 0-3; wherein Ar excludes substituted or unsubstituted indazol-3-yl and substituted or unsubstituted 1H-pyrazolo[3,4-b]pyridyl; with the following proviso: proviso IVa: when R₁₀ is hydroxyl or carbamoyl, Ar cannot be phenyl, 4-methyl-phenyl, 4-methoxy-phenyl, 4-halo-phenyl, or thiophen-yl when n is 0 or
 1. 23. The compound of claim 22 wherein Ar is selected from the group consisting of phenyl, substituted phenyl, thiophen-yl, substituted thiophen-yl, pyridinyl, substituted pyridinyl, thiazolyl, and substituted thiazolyl.
 24. The compound of claim 24 wherein Ar is selected from phenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-chloro-2-methoxyphenyl, 2-methoxy-4-(2-methyl-1H-imidazol-1-yl)phenyl, 1H-imidazol-1-yl-phenyl, 2-methyl-1H-imidazol-1-yl-phenyl, 1H-imidazol-1-yl-thiophen-2-yl, and 2-methyl-1H-imidazol-1-yl-thiophen-2-yl.
 25. The compound of claim 22 selected from the group consisting of: 3-(1-(4-carbamoylphenyl)-5-(3-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-phenyl-1-(4-ureidophenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-phenyl-1-(4-(sulfamoylamino)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-(2-amino-2-oxoethyl)phenyl)-5-phenyl-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-(2-amino-2-oxoethyl)phenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-methoxyphenyl)-1-(4-(methylcarbamoyl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-hydroxyphenyl)-5-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 2-(1-(4-hydroxyphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)acetic acid; 3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-hydroxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(5-(1H-imidazol-1-yl)thiophen-2-yl)-1-(4-hydroxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-acetylphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-(1-hydroxyethyl)phenyl)-5-phenyl-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-hydroxyphenyl)-5-(4-(2-methyl-1H-imidazol-1-yl)thiophen-2-yl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-methoxyphenyl)-1-(4-(pyridin-3-ylamino)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-methoxyphenyl)-1-(4-(1-methylpyrrolidin-3-yloxy)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-methoxyphenyl)-1-(4-(pyridin-4-ylamino)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-phenyl-1-(4-(2,2,2-trifluoroacetyl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-methoxyphenyl)-1-(4-(2,2,2-trifluoroacetyl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-(1H-imidazol-1-yl)phenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-chloro-2-methoxyphenyl)-1-(4-hydroxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-acetamidophenyl)-5-(4-chloro-2-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-carbamoylphenyl)-5-(4-chloro-2-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-chloro-2-methoxyphenyl)-1-(4-(methylsulfonamido)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-1-(4-(2-oxooxazolidin-3-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-(2-methyl-1H-imidazol-1-yl)thiophen-2-yl)-1-(4-(methylsulfonamido)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-acetamidophenyl)-5-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(2-methoxy-4-(2-methyl-1H-imidazol-1-yl)phenyl)-1-(4-(methylsulfonamido)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-acetamidophenyl)-5-(4-(2-methyl-1H-imidazol-1-yl)thiophen-2-yl)-1H-pyrrol-2-yl)propanoic acid; 3-(5-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-1-(4-(methylsulfonamido)phenyl)-1H-pyrrol-2-yl)propanoic acid; 3-(1-(4-(2-hydroxyethylamino)phenyl)-5-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-1H-pyrrol-2-yl)propanoic acid; and 3-(1-(4-hydroxyphenyl)-5-(5-(2-methyl-1H-imidazol-1-yl)thiophen-2-yl)-1H-pyrrol-2-yl)propanoic acid.
 26. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 22 together with a pharmaceutically accepted carrier or excipient.
 27. A method of treatment of a disease or condition which comprises administering a therapeutically effective amount of a compound of formula IV as defined in claim 22 to a patient in need thereof.
 28. A method of making a compound of formula IV as defined in claim
 22. 